Immunity Types Major Components And General Features Pathology Notes

Immunity

The normal immune system is essential for protection against infection. Immune system is like a double-edged sword. Though it is protective in most of situations, sometimes an hyperactive immune system may cause fatal diseases.

Immunity

Definition of Immunity: Immunity is resistance (defense mechanism) exhibited by host against invasion by any foreign antigen, including microorganisms.

Types of Immunity:

There are two types namely innate and adaptive immunity.

Innate (Natural/Native) Immunity:

General Features:

• First line of defense is present by birth.
• Provides immediate initial protection against an invading pathogen and can eliminate damaged cells.

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• Does not depend on prior contact with foreign antigen or microbes.
• Lacks specificity, but highly effective. No memory, and no self/non-self recognition.
• Triggers the adaptive immune response.
• No memory is seen.
• It functions in stages:
  • Recognition of microbes and damaged cells
  • Activation of various
  • mechanisms, and
  • Elimination of the unwanted substances.

Major Components of Immunity:

1. Physical/anatomical barriers: It includes epithelium lining skin, gastrointestinal and respiratory tracts act as mechanical barriers, produce anti-microbial molecules, such as defensins.

2. Cells:

Phagocytic cells: It consists of mainly monocytes (macrophages in tissue) and neutrophils in the blood. Phagocytic cells use several receptors to sense microbes and are called as “microbial sensors” (pattern recognition receptors).

• Pathogen-associated molecular patterns (PAMPs): Microbes have few highly conserved common molecular structures shared by entire classes of pathogens.
• These structures are called pathogen-associated molecular patterns (PAMPs) and are essential for the infectivity of these pathogens.
• Pattern-recognition receptors (PRRs): Phagocytic cells involved in innate immunity recognizes PAMP using a group of cellular receptors (microbial sensors) called pattern recognition receptors. Examples for PAMPs:
• Toll-like receptors (TLRs): These are transmembrane receptors and about 10 types of human TLRs have been identified. Each receptors recognize a unique set of microbial patterns.
• Receptors for mannose residues.
• NOD (nucleotide-oligomerization domain protein)-like receptors (NLRs) andthe inflammasome: They are located in the cytoplasm and serve as intracellular sensors for microbial products. Many NLRs signal via a cytosolic multiprotein complex called the inflammasome, which activates an enzyme (caspase-1).
• Receptors for opsonins.

Dendritic cells: These cells function as antigen-presenting cells to T cells. Thy produce type I interferons (IFN) (for example, IFN-α), which inhibit viral infection and replication.

Natural killer (NK) cells: They provide defense against many viral infections and other intracellular pathogens.

3. Soluble molecules in the blood and tissues:

• Complement system
• Proteins that coat microbes and aid in phagocytosis. e.g., mannose-binding lectin and C-reactive protein.

Functions of Innate Immune Response:

• Inflammation and destruction of invading microbe
• Antiviral defense is mediated by dendritic cells and NK cells.
• Provides the danger signals that stimulate the subsequent more powerful adaptive immune response.

Adaptive Immunity:

If the innate immune system fails to provide effective protection against invading microbes, the adaptive immune system is activated.

General Features:

• Second line of defense acquired during life
• Capable of recognizing both microbial and nonmicrobial substances
• Takes more time to develop and is more powerful than innate immunity
• Long-lasting protection
• Prior exposure to antigen is present
• Three characteristic features are:
  1. Specificity
  2. Diversity, and
  3. Memory.

Components of Immunity:

Write a short note on cellular immunity.
Or
Write a short note on humoral immunity.

• Humoral immunity: B lymphocytes and their soluble protein products called antibodies (also called immunoglobulins, Ig) and helper T cells.
• Cellular immunity: T lymphocytes and their soluble products called cytokines.

Functions of Adaptive Immune Response:

• Antibodies: Protection against extracellular microbes in the blood, mucosal secretions and tissues.
• T lymphocytes:
  • Defense against viruses, fungi and intracellular bacteria either by direct killing of infected cells by cytotoxic T lymphocytes or by activation of phagocytes to kill the ingested microbes.
  • Important immunoregulatory role, orchestrating and regulating the responses of other components of the immune system.

Different types of adaptive immunity and their diffrences are shown in Table.

Differences between two types of adaptive immunity:

Both B and T lymphocytes express highly specific receptors for a wide variety of substances, called antigens.

Cells Of The Immune System

Cells of immune responses (lymphocytes and other cells) migrate among lymphoid and other tissues and the vascular and lymphatic circulations.

Naïve Lymphocytes:

• These are mature lymphocytes that have not encountered the antigen (immunologically inexperienced).
• After the lymphocytes are activated by recognition of antigens, they differentiate into
• Effector cells: They perform the function of eliminating microbes.
• Memory cells: They live in a state of heightened awareness and are better able to combat the microbe in case it infects again.

T Lymphocytes:

• Development: T (thymus-derived) lymphocytes develop from precursors in the thymus.
• Distribution: Mature T cells are found in:
  • Peripheral blood where it constitute 60% to 70% of lymphocytes
  • T-cell zones of peripheral lymphoid organs namely the paracortical region of lymph node and periarteriolar sheaths of spleen.
• T-cell Receptor: T cell recognizes a specific cell-bound antigen by means of an antigen specific T-cell receptor (TCR).
• Markers: Leukocyte cell surface molecules are named systematically by assigning them a ‘cluster of differentiation (CD) antigen number that helps in their identification.
  • Primarily T-cell-associated CD molecules: CD1, CD3, CD4, CD5, and CD8.
  • CD3 is involved in signal transduction and is also known as pan T-cell marker.
• Subsets of T lymphocytes: Naïve T cells can differentiate into two subtypes namely CD4 and CD8. Both subtypes serve as “coreceptors” in T-cell activation. They are called as coreceptors because they work with the antigen receptor in responses to antigen.

B Lymphocytes:

• Development: B (bone marrow-derived) lymphocytes develop from precursors in the bone marrow.
• Distribution:
  • Peripheral blood: Mature B cells constitute 10% to 20% of the circulating peripheral lymphocyte population
  • Peripheral lymphoid tissues: Lymph nodes (cortex), spleen (white pulp), and mucosa-associated lymphoid tissues (pharyngeal tonsils and Peyer’s patches of GIT).
• B-cell Receptor (BCR): B cells have receptors composed of IgM and IgD on their surface and have unique antigen specificity.
• Functions of B cells: B cells recognize antigens via these BCRs.
  • Production of antibodies: The primary function of B cells is to produce antibodies and are the only cells in the body capable of producing antibody molecules (mediators of humoral immunity).
  • After stimulation by antigen and other signals, B cells develop into plasma cells. These cells secrete antibodies which are the mediators of humoral immunity.
  • Antigen-presenting cell: B cells also serve as APCs and are very efficient at antigen processing.
• Markers: B cell markers include: CD10 (CALLA), CD19, CD20, CD21 (EBV receptor), CD23, CD79a.

Dendritic Cells:

As the name suggests these cells have numerous fine cytoplasmic processes that resemble dendrites. These are important antigen-presenting cells (APC) in the body.

Macrophages of  Immunity:

• Macrophages are a part of the mononuclear phagocyte system.
• Role in adaptive immune responses:
  • Processing of antigen: Macrophages process the antigens present in the phagocytosed microbes and protein antigens. After processing, the antigen is presented to T cells and thus, they function as APCs in T-cell activation.
  • Effector cell in immunity:
    • Cell-mediated immunity: Macrophages are the main effctor cells in certain types of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes.
    • Humoral immunity: Macrophages also participate in the effector phase of humoral immunity.
    • Phagocytosis: Macrophages efficiently phagocytose and destroy microbes that are opsonized (coated) by IgG or C3b through their respective receptors.

Natural Killer Cells:

• Non-phagocytic large (little larger than small lymphocytes), granular (numerous
  cytoplasmic azurophilic granules) lymphocytes.
• Comprise about 5% to 15% of human peripheral lymphoid cells.
• Function: NK cells provide defense against many viral infections and other intracellular pathogens and also has antitumor activity, causing lysis of cells with which they react.

Cytokines

• Immune responses involve multiple interactions among many cells. These include lymphocytes, dendritic cells, macrophages, other inflammatory cells (for example,Neutrophils), and endothelial cells.
• Some of these interactions are cell-to-cell contact. However, many interactions and effector functions of leukocytes are mediated by short-acting soluble proteins called cytokines.

These cytokines represent the messenger molecules of the immune system and mediate communications between leukocytes are called interleukins.

Classification of Cytokines:

Most of the cytokines have many effects and can be classified depending on their functions.

Cytokines of Innate Immunity:

• These cytokines are produced rapidly in response to microbes and other stimuli
• Mainly secreted by macrophages, dendritic cells, and NK cells
• Mediate inflammation and anti-viral defense
• These cytokines include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines.

Cytokines of Adaptive Immune Responses:

• These cytokines are produced mainly by CD4+ T lymphocytes in response to antigen and other signals
• They promote lymphocyte proliferation and differentiation and activate effector cells
• This category include IL-2, IL-4, IL-5, IL-17, and IFN-γ.

Colony-stimulating Factors:

• These cytokines stimulate hematopoiesis and are assayed by their ability to stimulate the formation of blood cell colonies from bone marrow progenitors.
• They increase leukocyte numbers during immune and inflammatory responses.

Hypersensitivity: Immunologically Mediated Tissue Injury

• Immune response is usually a protective process but sometimes it may be injurious.
• Hypersensitivity means that the body responds to a particular antigen in an exaggerated fashion, which it does not happen in normal circumstances. Injurious immune reactions are called hypersensitivity.

Definition of  Hypersensitivity: A hypersensitivity reaction is a pathological, excessive, and injurious immune response to antigen leading to tissue injury, disease or sometimes death in a sensitized individual. The resulting diseases are named as hypersensitivity diseases.

General Features of Hypersensitivity Disorders:

Individuals who have been previously exposed to an antigen manifest detectable reactions to that antigen, i.e. the individual is said to be sensitized to that antigen. Hypersensitivity indicates an excessive or harmful reaction to the antigen.

• Priming or sensitization: It occurs in individuals who had previous contact with the antigen (allergen).
• Nature of antigens: It may be exogenous or endogenous origin.
  • Exogenous environmental antigens: Examples of environmental antigens (microbial and nonmicrobial) include antigens in dust, pollens, foods, drugs, microbes, chemicals, and few blood products.
  • Endogenous self antigens: Self or autologous antigens → cause autoimmune diseases.
• Genetic susceptibility: Hypersensitivity diseases (both allergic and autoimmune) are usually associated with the inheritance of particular susceptibility genes (for example, HLA genes).
• Imbalance between control and effector mechanisms: It produces damage to host tissues.
• In hypersensitivity reactions, the mechanisms of tissue injury are the same as the effctor mechanisms of defense against infectious pathogens.
• Hypersensitivity reactions are poorly controlled, excessive, or misdirected (for example, Against normally harmless environmental and self-antigens).

Classification of Hypersensitivity Reactions:

• Hypersensitivity diseases are classified on the basis of the immunologic mechanism that mediates the disease.
• This classification helps in distinguishing the manner in which the immune response causes tissue injury and disease, and also the pathological and clinical manifestations.
• However, multiple mechanisms may be operative in any one hypersensitivity disease.

Classification of hypersensitivity reaction according to the effector immune mechanism:

Type 1 (Immediate) Hypersensitivity

Write a short note on type I hypersensitivity reactions.

Usually known as allergic or atopic disorders and the environmental antigens that elicit these reactions are known as allergens.

Definition on type I hypersensitivity: Type 1 hypersensitivity reaction is a type of immunological tissue reaction, which occurs rapidly (within 5–10 minutes) after the interaction of antigen (allergen) with a IgE antibody on the surface of the mast cells in a previously sensitized person.

Characteristics of type 1 hypersensitivity reactions:

• The immediate reaction occurs within minutes (5–10 minutes).
• Antibodies: Mediated by IgE antibody.
• Develops after the interaction of an antigen with IgE bodies bound to mast cells.
• Genetic susceptibility: Occurs in genetically susceptible individuals previously sensitized to the antigen.
• Antigens (allergens): Many allergens (for example, House dust mites, pollens, animal danders or moulds) in the environment are harmless for the majority of individuals. Allergens elicit significant IgE reactions only in genetically predisposed individuals, who are said to be atopic.

The Sequence of Events :

During Initial Exposure to Antigen (Sensitization) In a genetically susceptible individual, the following events occur:

1. Exposure to sensitizing antigen: Individuals are exposed to environmental allergens and may be introduced by:

• Inhalation
• Ingestion, or Injection.

2. Presentation of the antigen: The sensitizing antigen (allergen) is presented to T cells. However, T cells do not recognize antigens by themselves but recognize when presented by APC (antigen-presenting cell), which captures the antigen.

3. Activation of T_H2 cells: In genetically susceptible individual, antigens (allergens) activates T_H2 subset of CD4+ helper T cells → secret cytokines (for example, IL-4, IL-5, and IL-13).

4. Production of IgE antibody: IL-4 secreted by T_H2 cells stimulates B cells to secrete cytotropic IgE antibodies.

5. Sensitization of mast cells by IgE antibody:

• Mast cells possess Fc-epsilon (FcεRI) receptors, which have a high affinity for IgE antibodies.
• IgE antibodies produced by B cells, attach to the FcεRI on the mast cells. These IgE antibody-bearing mast cells are sensitized to react if antigens bind to these antibodies.
• Eosinophils also express FcεRI and are involved in IgE-mediated defense against helminth infections.

During Subsequent Exposure to Antigen:

In a sensitized individual (the mast cell has attached IgE antibodies), during subsequent reexposure to the specific allergen, the following events occur:

• Mast cell activation: The antigen (allergen) binds to more than one IgE antibody molecule on mast cells → generates signals → causes mast cell degranulation → secretion of preformed (primary) mediators that are stored in the granules.

Two phases: IgE-triggered reactions can be divided into two phases:

1. Immediate response:
   • Develops within 5 to 30 minutes after exposure to an allergen and subsides in 60 minutes.
   • Characterized by vasodilation, vascular leakage, and smooth muscle spasm or glandular secretions.
2. Late-phase reaction:
   • Develops in 2 to 8 hours after the exposure to antigen which may last for several days.
   • Characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and T_H 2 cells. It also shows mucosal epithelial cell damage.

Mediators of Type I Hypersensitivity:

1. Preformed mediators (primary mediators): They are stored in mast cell granules. Their biological effcts start immediately following their release. These include:

• Vasoactive amines: Most important being histamine, which causes
  • Vasodilatation
  • Increased vascular permeability
  • Smooth muscle contraction
  • Increased secretion of mucus by nasal, bronchial, and gastric glands.
• Enzymes: These include neutral proteases (chymase, tryptase) and several acid hydrolases.
  • These enzymes cause tissue damage and generate kinins and activate components of complement (for example, C3a) by acting on their precursor proteins.
• Proteoglycans: It include heparin (anticoagulant), and chondroitin sulfate.
• Neutrophil and eosinophil chemotactic factors (NCF and ECF).

2. Secondary (newly synthesized) mediators:

• Lipid mediators: They are synthesized and secreted by mast cells, including leukotrienes and prostaglandins.
• Leukotrienes C₄ and D₄ (previously known as the slow-reacting substances of anaphylaxis-SRS-As):
• These are the most powerful (several thousand times more than histamine) and cause increased vascular permeability and bronchial smooth muscle contraction.
  • Leukotriene B₄: It is chemotactic for neutrophils, eosinophils, and monocytes.
  • Prostaglandin D₂: It causes bronchospasm and increased mucus secretion.
• Cytokines: Mast cells can produce many cytokines, which may be involved in immediate hypersensitivity reactions.

Clinical Manifestations of Type I Hypersensitivity:

Systemic Anaphylaxis:

• Acute, potentially fatal form and known as anaphylaxis (ana = without, phylaxis = protection).
• Usually follows injection of an antigen into a sensitized individual.
• May cause shock and death.

Causes of Anaphylaxis: It develops.

• After administration of foreign proteins (for example, A antisera), drugs ( for example, Penicillin), hormones, and enzymes
• Following exposure to food allergens (for example, Peanuts, Shellfih) or insect toxins (for example, Bee venom)

Dose: Systemic anaphylaxis may be triggered by extremely small doses of antigen.

Clinical features of Anaphylaxis :

• Itching, hives, and skin erythema appear within minutes after exposure
• Followed by difficulty in breathing and respiratory distress due to the contraction of respiratory bronchioles
• Laryngeal edema results in hoarseness and laryngeal obstruction, which further aggravates respiratory difficulty
• Vomiting, abdominal cramps, and diarrhea may follow
• May lead to shock and death within the hour.

Local Reactions:

• Recurrent and non-fatal.
• Site of local reaction depends on the portal of entry of the allergen.
• Causes: Develop against common environmental allergens, such as pollen, animal dander, house dust, and foods.

Atopy:

• Susceptibility to type 1 hypersensitivity reactions is genetically determined. Atopy refers to a familial predisposition to produce exaggerated localized immediate hypersensitivity (IgE mediated) reactions to inhaled and ingested environmental substances (allergens) that are otherwise harmless.
• Atopic individuals tend to have higher serum IgE levels, and more IL-4–producing T_H2 cells.
• A positive family history of allergy is found in 50% of atopic individuals.

Examples of type 1 hypersensitivity reactions are listed in Table.

Examples of type I hypersensitivity reactions:

Antibody-Mediated (Type 2) Hypersensitivity

Write a short note on type 2 hypersensitivity reactions.

Definition Type 2 hypersensitivity: Type 2 hypersensitivity disorders are caused by antibodies (IgG/IgM), which react with target antigens on the surface of cells or found in the extracellular matrix. These antibodies cause disease by destroying the involved cells, triggering inflammation, or interfering with normal functions.

Characteristics of Type 2 hypersensitivity: 

1. Antibodies: IgG (usually) and IgM (rarely) type of antibodies mediate type II reactions.

2. Antigen: It may be endogenous or exogenous

• Endogenous antigens: It may be normal molecules intrinsic to the cell membrane or extracellular matrix (for example,Autoimmune diseases).
• Exogenous antigens: These antigens may get adsorbed on a cell surface or extracellular matrix → may cause altered surface antigen (for example,Drug metabolite).

Mechanisms of Injury of Type 2 Hypersensitivity:

Mechanism of tissue injury can be broadly divided into:

1. Complement dependent
2. Atibody-dependent.

Complement Dependent Reactions:

1. Opsonization and phagocytosis: Complement injure the target cells by promoting their phagocytosis.

• Production of antibodies: Antigen may be intrinsic to target cells (for example, RBC or platelets) or exogenous antigen adsorbed to its cell surface. B cells produce IgG antibodies (for example, Autoantibodies) against target antigens.
• Activation of complement: Antigen-antibody complexes are formed on the surfaces of the target cells → may activate the complement system by the classical pathway.
• Opsonization: Complement components such as C3b, which act as opsonins and get deposited on the surfaces of the target cells.
• Phagocytosis: Opsonized cells are recognized by phagocytes through Fc and C3b receptors on its surface → results in phagocytosis of the opsonized cells → destruction of cells by phagocytes (for example, Macrophages in spleen).

Examples:

• Autoimmune hemolytic anemia: The target antigen is RBC membrane protein (Rh or I antigen).
• Autoimmune thrombocytopenia purpura: The target antigen is GpIIb/IIIa of platelets
• Drug-induced hemolytic anemia.

2. Lysis of target cells through membrane attack complex :

• Complement causes lysis of target cells by generating membrane attack complex (C5-9)
• Complement activation on cells also generates membrane attack complex (MAC).
• MAC disrupts membrane integrity and causes lysis of the cells.

Example: Transfusion reactions in which the cells from an incompatible donor react with and are opsonized by a preformed antibody in the recipient. Hemolytic disease of newborn.

3. Tissue injury by complement and Fc receptor-mediated inflammation:

Complement induces inflammation and causes injury to target cells.

• Antibodies against matrix components in field tissue antigens, such as basement membranes and extracellular matrix may activate the complement system by the classical pathway.
  • Complement components may cause injury due to inflammation. This may be due to
  • Chemotactic agents (mainly C5a) produced at the site of deposition of antibody and
  • Anaphylatoxins (C3a and C5a), which increase vascular permeability.
• Activated inflmmatory cells (leukocytes) release lysosomal enzymes and reactive oxygen species which damage tissues.
• Inflmmation may also be induced by antibody binding to Fc receptors of leukocytes

Example: Goodpasture syndrome in which an anti-glomerular basement membrane antibody binds to a glomerular basement membrane antigen and activates the complement system. The recruitment of inflammatory cells damages the basement membrane.

 Antibody-dependent (Complement Independent) Cellular Dysfunction:

It is characterized by the deposition of antibodies against target cell surface receptors, which may impair or dysregulate the function of the target cell without causing cell injury or inflammation.

Examples:

• Antibody-mediated stimulation of cell function: In Graves’ disease, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells. This results in hyperthyroidism
• Antibody-mediated inhibition of cell function: In myasthenia gravis, antibodies directed against acetylcholine receptors in the motor end plates of skeletal muscles block neuromuscular transmission. This causes muscle weakness.

Mechanism of type 2 hypersensitivity reactions are summarized:

Examples of type 2  hypersensitivity diseases are presented in Table.

Examples of type 2 hypersensitivity (antibody-mediated) diseases:

Immune Complex–Mediated (Type 3) Hypersensitivity

Write a short note on type 3 hypersensitivity reactions.

Definition of type 3 hypersensitivity reactions: Type 3 hypersensitivity reactions are characterized by the formation of immune (antigen and antibody) complexes in the circulation and may get deposited in blood vessels, leading to complement activation and acute inflammation.

The inflammatory cells recruited (neutrophils and monocytes) release lysosomal enzymes → generate toxic free radicals → cause tissue damage.

Characteristics of type 3 hypersensitivity reactions:

1. Antibodies: Complement-fixing antibodies namely IgG, IgM, and occasionally IgA.
2. Antigen:
   • Exogenous: Various foreign proteins, for example, Foreign serum protein injected (for example, Diphtheria antitoxin, horse anti-thymocyte globulin) or produced by an infectious microbe.
   • Endogenous: Antibody against self-components (autoimmunity), for example, Nucleoproteins.

Sites of Antigen-antibody Formation:

• Circulating immune complexes: They are formed within the circulation.
• In situ immune complex: Less frequently, the immune complexes may be formed at sites where antigen has been “planted” previously producing in situ immune complexes.

Sites of Immune Complex Deposition:

• Systemic: Circulating immune complexes may be deposited in many organs.
• Localized: Immune complexes may be deposited or formed in particular organs/tissues: kidney (glomerulonephritis), joints (arthritis), and small blood vessels of the skin.

Cause of Tissue Damage:

• Activation of complement
• Inflammation at the sites of deposition

Examples of immune complex disorders are listed in Table

Examples of immune complex-mediated diseases:

Systemic Immune Complex Disease — Acute Serum Sickness:

Write a short note on serum sickness.

This was a frequent sequela to the administration of large amounts of foreign serum (for example, Serum from immunized horses used for protection against diphtheria). Nowadays it is infrequent.

Pathogenesis on serum sickness:

Divided into three phases:

1. Formation of immune complexes:

• Introduction of protein antigen: It initiates an immune response.
• Formation of antibody: It usually forms a week (7 to 12 days) after the injection of the foreign protein and is secreted into the blood.
• Formation of immune complexes: They are formed in the circulation when antibodies react with the antigen.

2. Deposition of immune complexes:

Immune complexes of medium size and with slight antigen excess are the most pathogenic.

Sites of deposition:

• Blood vessels: It causes vasculitis.
• Renal glomeruli: It causes glomerulonephritis.
• Joints: It causes arthritis.

3. Inflammatory reaction and tissue injury: Mechanisms of tissue injury include:

• Inflammatory reaction: Immune complexes in the tissues activates complement, the products (for example, Chemotactic C5a) of which causes chemotactic recruitment of acute inflammatory cells (neutrophils and monocytes) to the site.
• Tissue damage: Activated inflammatory cells (leukocytes) release lysosomal enzymes, arachidonic acid products, and reactive oxygen species → which produce tissue damage.

Clinical features of serum sickness:

Fever, urticaria, joint pains (arthralgias), lymph node enlargement, and proteinuria appear during this phase.

Morphology on serum sickness:

• Acute necrotizing vasculitis: It is the main feature and is characterized by necrosis of the vessel wall
  and intense neutrophilic infiltration.
• Fibrinoid necrosis: It consists of necrotic tissue, immune complexes deposits, complement, and plasma protein. It produces a smudgy eosinophilic appearance at the site of the deposit and obscures the cellular detail.

Local Immune Complex Disease—Arthus Reaction:

Write a short note on Arthus’s reaction.

Differences between serum sickness and Arthus reaction.

• Arthus reaction is a local area of tissue necrosis usually in the skin, resulting from acute immune complex vasculitis.
• Arthus reaction can be experimentally produced by intracutaneous injection of an antigen into a previously immunized animal (with circulating antibodies against the antigen).
• As the antigen diffuses into the vascular wall, it locally binds to the antibody and forms large immune complexes at the site of injection.
• Immune complexes deposited in the vessel walls cause fibrinoid necrosis, and thrombosis leading to ischemic injury.

T Cell-Mediated (Type 4) Hypersensitivity

Write a short note on type 4 hypersensitivity reactions/delayed hypersensitivity reactions.

• Type 4 hypersensitivity reaction is mediated by T lymphocytes including CD4+ and CD8+ T cells.
• It develops in response to antigenic exposure in a previously sensitized individual.
• The reaction is delayed by 48 to 72 hours after exposure to antigen. Hence also called as delayed-type hypersensitivity (DTH).
• This hypersensitivity reaction is involved in several autoimmune diseases (for example, Rheumatoid arthritis, Hashimoto thyroiditis), pathological reactions to environmental chemicals (for example,
  Poison ivy, nickel) and persistent microbes (for example, Tuberculosis, leprosy).

Types type 4 hypersensitivity reactions:

Two types namely:

1. Cytokine mediated inflammation in which CD4+ T cells produce cytokines and
2. Direct cell toxicity mediated by CD8+ T cells.

Cytokine Mediated Inflammation Elicited By CD4+ T Cells:

1. First exposure to antigen:

• Type of antigen: The antigen may be either exogenous environmental antigens or endogenous (self-antigens causing autoimmune disease).
• Processing of antigen: Upon exposure to an antigen, it should be processed by the antigen-presenting cells (APC- dendritic cells or macrophages) before presenting it to
  • T cells, because T cells cannot directly recognize the antigen.
  • Recognition of antigen by naïve CD4+ T cells in association with II MHC molecules on APC.
• Diffrentiation of CD4+ T cells:
  • If the APCs secrete IL-12, the naïve CD4+ T cells diffrentiate into effctor cells of T H1 type.
  • If the APCs secrete IL-1, Il-6, or IL-23 (instead of IL-12), the naïve CD4+ T cells differentiate into effector cell of T H17 type.

2. On repeat exposure to an antigen: Previously activated T cells recognize the antigen presented by APCs. Depending on the cytokines produced, one of two effector cells, i.e. either T
H1 or TH17 cells respond.

• T H1 cells → production of cytokines (for example, IFN-γ and TNF). IFN-γ (most powerful macrophage activating cytokine) → activates macrophages.
  • Activated macrophages have increased phagocytic and microbicidal power. Thysecrete IL-12 which amplifies the TH1 response.
• TH17 cells: They are activated by some microbial antigens as well as self-antigens in autoimmune diseases. They produce IL-17, IL-22, chemokines, and other cytokines. These cytokines promote inflmmation by recruiting more neutrophils and monocytes to the site of reaction.

Tuberculin Reaction (Montoux Test):

• Tuberculin reaction is a classical example of delayed-type hypersensitivity.
• It is produced by the intracutaneous injection of purifid protein derivative (PPD, also called tuberculin), a protein-containing antigen of the tubercle bacillus.
• In a previously sensitized individual, the injection site becomes red and indurated in 8 to 12 hours, reaches a peak (usually 1 to 2 cm in diameter) in 24 to 72 hours, and thereafter slowly subsides.
• Microscopically, the injected site shows perivascular accumulation “cuff” of CD4+ T cells and macrophages.

Contact Dermatitis:

Contact with various environmental antigens (for example, Poison ivy, metals such as nikel and chromium, chemicals like hair dyes, cosmetics, and soaps) may evoke inflmmation with blisters in the skin at the site of contact known as contact dermatitis.

Direct Cell Toxicity Mediated By CD8+ T Cells:

• It is a type of T-cell mediated tissue injury due to CD8+ T lymphocytes (also called as cytotoxic
• T lymphocytes- CTLs), which kill antigen-bearing target cells.
• Example: The killing of virus-infected cells (n for example, Iviral hepatitis) and some tumor cells.

Examples of T cell-mediated (type 4) hypersensitivity are shown in Table.

Examples of T cell-mediated (type 4) hypersensitivity

Salient features and differences between hypersensitivity reactions are presented in table.

Salient features and differences between hypersensitivity reactions:

Autoimmune Diseases

Definition of Autoimmunity: Autoimmunity is defined as immune reactions in which the body produces autoantibodies and immunologically competent T- lymphocytes against self-antigens.

Autoimmunity is an important cause of certain diseases in humans:

• Organ-specific disease: It may be restricted to a single organ or tissue (for example, Type 1 diabetes).
• Systemic or generalized disease: For example,Systemic lupus erythematosus (SLE).
• Involving more than one organ: For example, Goodpasture’s syndrome, in which lung and kidney are involved.

Normal individuals are unresponsive (tolerant) to their own (self) antigens and autoimmune disorders result from the loss of self-tolerance.

Immunological Tolerance:

List autoimmune diseases:

• Immunological tolerance is the phenomenon in which there is no immune response to specific (usually self) antigens. It is the result of exposure of lymphocytes to that specifi antigen.
• Self-tolerance: It is absence of an immune response to an individual’s own antigens.

Examples of autoimmune diseases:

Autoimmunity develops from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers (for example, infections and tissue damage), which promote the activation of self-reactive lymphocytes.

General Features of Autoimmune Diseases:

• Autoimmune diseases are usually chronic, sometimes with relapses and remissions.
• Damage caused is often progressive.
• Clinical and pathological features of an autoimmune disease depend on the nature of the underlying immune response.

Systemic Lupus Erythematosus (SlE)

SLE is a chronic autoimmune disease having the following characteristics:

1. Protean manifestation and variable behavior.
2. Remission and relapses.
3. Multisystemic involvement: Mainly affects skin, kidneys, joints, serous membranes, and heart.
4. A broad spectrum of autoantibodies, the most important is antinuclear antibodies (ANAs).

Etiology of SLE:

SLE is an autoimmune disease in which a fundamental defect is the failure of self-tolerance. It leads to the production of many autoantibodies that damages the tissue either directly or indirectly by depositing immune complex deposits. A combination of genetic and environmental factors plays a role in the pathogenesis of SLE.

Genetic Factors of SLE:

Evidence to support genetic predisposition are:

1. Familial association:

• Family members of SLE patients have an increased risk of SLE. About 20% of unaffected fist-degree relatives may show autoantibodies.
• High rate of concordance (>25%) in monozygotic twins when compared with dizygotic twins (1%–3%).

2. HLA association: Risk is more with HLA-DR2 or HLA-DR3.

3. Other genetic factors:

• Genetic deficiencies of early complement components (such as C2, C4, or C1q): It may result in:
  • Impaired removal of circulating immune complexes by the mononuclear
    phagocyte system
  • Defective phagocytic clearance of apoptotic cells and 3) failure of
  • B cell tolerance. If apoptotic cells are not cleared, their nuclear components may elicit immune responses.
• Polymorphism in the inhibitory Fc receptor → inadequate control of B cell activation.

Immunological Abnormalities of SLE:

Several immunological abnormalities of both innate and adaptive immune systems have been observed in SLE.

1. Type 1 interferons:

• These are antiviral cytokines normally produced by B cells during innate immune responses to the nucleic acid of viruses.
• INF-α is a type I interferon produced by plasmacytoid dendritic cells and large amounts is produced in SLE. It may indirectly produce autoantibodies.

2. TLR signals:

• TLRs present in B lymphocytes normally sense microbial products, including nucleic acids.
• In SLE, nuclear DNA and RNA within the immune complexes may activate B lymphocytes by engaging with TLRs.
• These activated B cells specific for nuclear antigens may produce antinuclear autoantibodies.

3. Failure of B cell tolerance: Occurs due to defects in both central (i.e. bone marrow) and peripheral tolerance → higher autoreactive B cells.

Environmental Factors of SLE:

1. Ultraviolet (UV) radiation: Exposure to sunlight exacerbates the lesions of the disease.
2. Mechanism: UV irradiation → causes apoptosis of host cells → increases the burden of nuclear antigens and promotes inflmmation.
3. Cigarette smoking: It is associated with the development of SLE.
4. Sex hormones: SLE is 10 times greater during the reproductive period (17–55 years) in women than in men. SLE shows exacerbation during normal menses and pregnancy.
5. Drugs: Examples include hydralazine, procainamide, isoniazid, and d-penicillamine can produce SLE–like disease and disease remits after withdrawal of the drug.

Pathogenesis of SLE:

Different steps are:

1. Increased apoptosis triggered by environmental agents: UV irradiation and other environmental agents may cause the death of cells by apoptosis.
2. Inadequate clearance of apoptotic bodies: It results in the accumulation of large amounts of nuclear antigens. It is partly due to defect in complement proteins.
3. Susceptibility genes with failure of self-tolerance: Genetic abnormality in B and T lymphocytes is responsible for failure of self-tolerance.
4. Stimulation of self-reactive B cells: It produces antibodies against the self-nuclear antigens.
5. Formation of antigen-antibody (immune) complexes in the circulation.
6. Endocytosis of immune complexes: Th antibodies portion of immune complexes bind to Fc receptors on B cells and dendritic cells (DCs), and the immune complexes may be internalized by endocytosis.
7. TLR engagement by nuclear antigens: Nucleic acid components of immune complexes bind to TLRs (Toll-like receptors) of B cells and DCs.
8. TLR stimulation of B cells and DCs: Binding to TLR
   • Stimulate B cells to produce autoantibodies
   • Activate dendritic cells (mainly plasmacytoid DCs) to produce INF-α → stimulate B and T cells to further amplify immune response → cause more apoptosis.
9. Persistent production of autoantibodies: Thus, a cycle of antigen release and immune activation → results in the persistent production of IgG autoantibodies.

Autoantibodies in SLE:

• SLE is characterized by the production of several diverse autoantibodies. Some antibodies are against different nuclear and cytoplasmic components of the cell that are not organ-specific.
• Other antibodies are directed against specific cell surface antigens of blood cells.
• Antinuclear antibodies (ANAs): They are directed against various nuclear antigens including DNA, RNA, and proteins (all together called generic ANAs), and can be grouped into different categories.

Important antinuclear antibodies and their clinical utility:

Mechanisms of Tissue Injury:

Autoantibodies mediate tissue injury.

• Type 3 hypersensitivity: It occurs with the deposition of immune complexes. It is the most common cause of tissue injury and visceral lesions.
• Type 2 hypersensitivity: Autoantibodies against cell surface antigens specific for RBCs, white cells, and platelets → opsonize these cells → promote their phagocytosis and lysis → cytopenias.

LE Bodies or Hematoxylin Bodies:

Write a short note on LE cell.

LE Bodies:

• ANAs cannot penetrate intact cells, but if nuclei of the cell are exposed, they can bind to them.
• In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and appear homogeneous, to produce LE bodies or hematoxylin bodies.
• It is related to LE bodies and can be demonstrated in vitro.
• The blood sample is agitated to damage the nucleated cells and it releases the nuclei.
• The nuclei of damaged cells react with ANAs to form a homogenous
  denatured nuclear material.
• The LE cell is any phagocytic leukocyte (blood neutrophil or macrophage) that has engulfed this denatured nucleus of an injured cell.
• With the advent of new techniques for the detection of ANAs, this test is of only historical interest.
• Sometimes, LE cells can be found in body fluid, such as pericardial or pleural effusions.

Morphology of LE cell:

• SLE is a systemic autoimmune disease and morphologic changes in SLE are extremely variable.
• The most characteristic lesions of SLE are due to the deposition of immune complexes in blood vessels, kidneys, connective tissue, and skin.

Kidney on LE cell:

• The kidney may be involved in about 50% of SLE patients and is one of the most important organs involved.
• However, it involves tubules and interstitium.
• Pathogenesis of glomerulonephritis: Immune complexes composed of DNA and anti-DNA antibodies get deposited in the glomeruli → inflammation → proliferation of cells (endothelial, mesangial, and/or epithelial).

Morphologic classification of lupus nephritis: Six patterns are recognized but none of these is specific for SLE:

1. Minimal mesangial lupus nephritis (class 1)
2. Mesangial proliferative lupus nephritis (class 2)
3. Focal proliferative lupus nephritis (class 3)
4. Diffuse proliferative lupus nephritis (class 4)
5. Membranous lupus nephritis (class 5)
6. Advanced sclerosing lupus nephritis (class 6)

Clinical Features on LE Cell:

SLE is a multisystem disease with variable clinical presentation.

• Age: It usually occurs in young women between 20 to 30 years, but may manifest at any age.
• Sex: It predominantly affects women, with a female-to-male ratio of 9: 1.
• Onset: Acute or insidious with fever.
• Typical presentation: Butterfly rash over the face, fever, pain without deformity in one or more peripheral joints, pleuritic chest pain, and photosensitivity. SLE patients are susceptible to infections, because of immune dysfunction and treatment with immunosuppressive drugs.

Major Histocompatibility Complex (Mhc) Molecules

• All human cells have a series of molecules on their surfaces that are recognized by other individuals as foreign antigens.
• Major histocompatibility complex (MHC) molecules were discovered as products of genes that evoke rejection of transplanted organs and are responsible for tissue compatibility between individuals.
• The human major histocompatibility complex (MHC) are commonly called the human leukocyte antigen (HLA) complex is the name of the loci of genes densely packed (clustered) on a small segment on chromosome 6 (6p21.3).
• They were named HLA because in humans MHC-encoded proteins were initially detected on leukocytes by the binding of antibodies.

Physiologic function of MHC molecules: To display peptide fragments of proteins for recognition by antigen-specific T cells.

• The MHC molecules are products of the MHC gene. The best-known of these genes are the HLA class 1 and class 2 genes.
• Their products are important for immunologic specificity and transplantation histocompatibility, and they play a major role in susceptibility to a number of autoimmune diseases.

Polymorphism of MHC gene:

• The MHC gene is highly polymorphic. Polymorphism means that there are many alleles of each MHC gene resulting in extreme (high degree) variation in the MHC in human population (genetic diversity).
• Each person inherits one set of these alleles that is different from the alleles in most other persons. The possibility of two different individuals having the same combination of MHC molecules is very remote.
• Threfore, grafts exchanged between individuals are recognized as foreign and attacked by the immune system.
• Polymorphism is an important barrier in organ transplantation.
• HLA haplotype: It is the combination of HLA alleles in each individual. Each individual inherits one set of HLA genes from each parent and thus typically expresses two diffrent molecules for every locus.

Importance of MHC:

1. In organ/tissue transplantation and
2. HLA is linked to many autoimmune diseases.

Classification of MHC:

• MHC gene product is classified based on their structure, cellular distribution, and function into three groups
• MHC class I and class II gene products are critical for immunologic specificity and transplantation histocompatibility, and they play a major role in susceptibility to a number of autoimmune diseases.

Class 1 MHC Molecules:

• They are the products of MHC class I genes and are expressed on all nucleated cells and platelets (except erythrocytes and trophoblasts).
• They are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C.
• Highly polymorphic in the population and the most highly polymorphic segment known within the human genome.

Functions of Class 1 MHC Molecules:

• Products of the MHC class I gene are integral participants in the immune response to intracellular infections, tumors, and allografts.
• Class 1 MHC molecules display peptides that are derived from proteins, such as viral and tumor antigens, that are located in the cytoplasm.
• These peptides are usually produced in the cell.
• The class 1–associated peptides are recognized by CD8+ T lymphocytes. Class I molecules interact with CD8+ T lymphocytes during antigen presentation and are involved in cytotoxic reactions.
• CD8+ T lymphocytes recognize antigens only in the context of selfless I molecules, they are referred to as class 1 MHC-restricted.

Class 2 MHC Molecules:

• They are encoded in a region called HLA-D, which has three sub-regions: HLA-DP, HLA-DQ, and HLA-DR.
• Class 2 antigens (HLA-D and -DR, D-related) are expressed only on professional antigen-presenting cells (B lymphocytes, monocytes/macrophages, Langerhans’ cells, dendritic cells) and activated T cells.

Function Class 2 MHC Molecules:

• Class 2 MHC molecules present antigens that are internalized into vesicles, and are usually derived from extracellular microbes and soluble proteins.
• The HLA-D locus contains genes that encode many proteins involved in antigen processing and presentation.
• The class 2 peptide complex is recognized by CD4+ T cells (function as helper cells) and this CD4 molecule acts as the co-receptor.
• Because CD4+ T cells can recognize antigens only in the context of self–class II molecules → they are referred to as class II MHC–restricted.

Class 3 MHC Molecules:

Their gene encodes components of the complement system, cytokines, tumor necrosis factor (TNF), lymphotoxin, and some proteins without apparent role in the immune system.

Acquired Immunodeficiency Syndrome (AIDS)

AIDS is caused by the retrovirus human immunodeficiency virus (HIV).

Characteristic Features of AIDS:

• Infection and depletion of CD4+ T lymphocytes.
• Severe immunosuppression → leads to opportunistic infections, secondary neoplasms, and neurologic manifestations.

Route of Transmission:

Transmission of HIV occurs when there is an exchange of blood or body fluids containing the virus or virus-infected cells. The three major routes of transmission are:

1. Sexual transmission: It is the main route of infection in more than 75% of cases of HIV.

1. Homosexual or bisexual men or heterosexual contacts: It may be male-to-male or male-to-female or female-to-male transmission.
2. HIV is present in genital fluids, such as vaginal secretions and cervical cells (in women), and semen (in men).
3. The risk of sexual transmission of HIV is increased when there is coexisting sexually transmitted diseases, especially those associated with genital ulceration (for example,Syphilis, Chancroid, and herpes).
4. Viral transmission can occur in two ways:
   • Direct inoculation of virus or infected cells into the blood vessels at the site of breach caused by trauma, and
   • By uptake into the mucosal dendritic cells (DCs).

2. Parenteral transmission: Three groups of individuals are at risk:

1. Intravenous drug abusers: Transmission occurs by sharing of needles, and syringes contaminated with HIV-containing blood.
2. Hemophiliacs: Mainly those who received large amounts of factor VIII and factor 9 concentrates before 1985. Now increasing use of recombinant clotting factors have eliminated this mode of transmission.
3. Transfusion of blood or blood components:
   • Recipients of blood transfusion of HIV-infected whole blood or components (for example, Platelets, plasma) was one of the modes of transmission.
   • Screening of donor blood and plasma for antibody to HIV has reduced the risk of this mode of transmission.
   • Because of recently infected individual may be antibody-negative (seronegative), there is a small risk of acquiring
   • AIDS through transfusion of blood. Organs from HIV-infected donors can also transmit AIDS.

3. Perinatal transmission (mother-to-infant transmission):

• Major mode of transmission of AIDS in children.
• Transmission of infection can occur by three routes:
  • In utero: It is transmitted by transplacental spread.
  • Perinatal spread: During normal vaginal delivery or childbirth (intrapartum) through an infected birth canal and in the immediate period (peripartum).
  • After birth: It is transmitted by ingestion of breast milk or from genital secretions.

Transmission of HIV infection to healthcare workers: There is an extremely small risk of transmission to healthcare professionals, after accidental needle-stick injury or exposure of nonintact skin to infected blood.

Etiology  of AIDS:

1. Properties of HIV:

• AIDS is caused by HIV, which is a non-transforming human retrovirus belonging to the lentivirus family.
• Retroviruses are RNA viruses having an enzyme called reverse transcriptase, which prepares a DNA copy of the RNA genome of the virus in host cell.

Genetic forms: HIV occurs in two genetically different but related main forms, HIV-1 and HIV-2.

• HIV-1 is most common in the United States, Europe, and Central Africa.
• HIV-2 is common in West Africa and India.

2. Structure of HIV:

Write a short note on the structure of HIV.

• HIV-1 is a spherical enveloped virus that is about 90–120 nm in diameter.
• It consists of an electron-dense, cone-shaped core surrounded by a nucleocapsid cell which is covered by a lipoprotein envelope.

1. Viral core: It contains

• Major capsid protein p24: Ths viral antigen and the antibodies against this are used for the diagnosis of HIV infection in enzyme-linked immunosorbent assay (ELISA).
• Nucleocapsid protein p7/p9.
• Two identical copies of single-stranded RNA genome.

Three viral enzymes:

• Protease
• Reverse transcriptase (RNA-dependent DNA polymerase), and
• Integrase. When the virus infects a cell, viral RNA is not translated, but instead transcribed by reverse transcriptase into DNA.

The DNA form of the retroviral genome is called a provirus which can be integrated into the chromosome of the host cell.

2. Nucleocapsid: The viral core is surrounded by a matrix protein p24 and p17, which lies underneath the lipid envelope of the virion.

3. Lipid envelope: The virus contains a lipoprotein envelope, which consists of lipid derived from the host cell and two viral glycoproteins.

These glycoproteins are:

1. gp120 which project as knob-like spikes on the surface and
2. gp41 anchoring transmembrane pedicle.

These glycoproteins are essential for HIV infection of cells.

3. HIV Genome:

It contains two main groups of genes and their products act as antigens.

1. Standard genes: HIV-1 RNA genome contains three standard retroviral genes, which are typical of retroviruses.
2. Thse include Gag, Pol, and env Genes. Initially, the protein products of the gag and pol genes are translated into large precursor proteins and are later cleaved by the viral enzyme protease to form → mature proteins.
3. Accessory genes: HIV contains accessory genes: e.g. tat, rev, vif, nef, vpr, and vpu. They regulate the synthesis and assembly of infectious viral particles and the pathogenicity of the virus.

Pathogenesis of HIV Infection and AIDS:

Write a short note on the pathogenesis of HIV infection and AIDS.

Infection is transmitted when the virus enters the blood or tissues of an individual.

Major targets: HIV can infect many tissues, but two major targets of HIV infection are the:

• Immune system
• Central nervous system (CNS).

Life Cycle of HIV:

Question 12. Write a note on life cycle of HIV.
Answer:

Consists of four main steps namely:

1. Infection of cells by HIV
2. Integration of the provirus into the host cell genome
3. Activation of viral replication, and
4. production and release of infectious virus

1. Infection of Cells by HIV:

• Cell tropism: HIV has a selective affinity for host cells with CD4 molecule receptors. The cells with such receptors include CD4+ T cells and other CD4+ cells such as monocytes/ macrophages and dendritic cells.
• The HIV envelope contains two glycoproteins, surface gp120 noncovalently attached to a transmembrane protein, gp41.
• Gp120 of HIV binding to CD4 molecule receptors on the host cell is the first step in HIV infection. Binding alone is not enough for infection and requires the participation of a coreceptor molecule.
• Conformational change: Binding to CD4 leads to a conformational change in the HIV, which results in the formation of a new recognition site on gp120 for the coreceptors
• CCR5 or CXCR4.
• Gp120 binding to chemokine receptor: New recognition site on gp120 of HIV binds to chemokine receptors, i.e. CCR5 and CXCR4.
• Penetration of host cell membrane by gp41: Binding of gp120 to the chemokine coreceptors leads to conformational changes in gp41.
• Membrane fusion: Th conformational change in gp41 allows HIV to penetrate the cell membrane of the target cells (e.g. CD4+ T cells or macrophages), leading to fusion of the virus with the host cell.
• Entry of viral genome into cytoplasm of host cell: Once internalized, the virus core containing the HIV genome enters the cytoplasm of the host cell.

2. Integration of the proviral DNA into the genome of the host cell

After the internalization of the virus core, the RNA genome of the virus undergoes reverse transcription → leading to the synthesis of double-stranded complementary DNA (cDNA/proviral DNA).

• Episomal form: In quiescent T cells, HIV cDNA may remain as a linear episomal form in the cytoplasm of infected cells.
• Integration of cDNA: In dividing T cells, HIV cDNA enters the nucleus, and becomes integrated into the genome of the host cell using a viral integrase protein.

3. Viral replication: After the integration of proviral DNA it can either be latent or productive infection.

• Latent infection: During this, the provirus remains silent for months or years.
• Productive infection: In this the proviral DNA is transcribed → leading to viral replication → formation of complete viral particles.

4. Production and release of infectious virus: The complete virus particle forms, buds from the cell membrane, and release new infectious virus.

• This productive infection when extensive, leads to the death of infected host cells.
• The virus infection remains latent for long periods in lymphoid tissues.
• Active viral replication is associated with more infection of cells and progression to AIDS.
• Dissemination: The virus disseminates to other target cells.
• This occurs either by fusion of an infected cell with an uninfected one or by the budding of virions from the membrane of the infected cell.

Progression of HIV Infection:

1. Acute Infection:

HIV infection starts as an acute infection. It is only partially controlled by the host immune response and progresses to chronic infection of peripheral lymphoid tissue.

• Primary infection: HIV fist infects memory CD4+ T cells (express CCR5), which are present in the mucosal lymphoid tissue (the largest reservoir of T cells and where the majority of memory cells are lodged). HIV causes the death of these cells resulting in signifiant depletion of T cells.
• Spread to lymphoid tissue: Dendritic cells at the primary site of infection capture the virus and migrate to lymphoid tissue such as lymph nodes and spleen. In the lymphoid tissues, DCs is passed on to CD4+ T cells by direct cell-to-cell contact.
• Acute HIV syndrome: Virus replicates and causes viremia, accompanied by acute HIV syndrome (nonspecific signs and symptoms similar to many viral diseases).
• Host immune response against HIV: Virus spreads throughout body and infects helper T cells, macrophages, and DCs in the peripheral lymphoid tissues. During this period, the host humoral and cell-mediated immune response develops against viral antigens.
• These include anti-HIV antibodies and HIV-specific cytotoxic T cells. Immune responses partially control the infection and viral replication.

2. Clinical Latency Period:

Following acute phase it progresses to chronic phase. This phase is characterized by the dissemination of virus, viremia, and the development of an immune response by host.

• Minimal/no symptoms: In this phase, virus continuously replicates in the lymph nodes and spleen.
• Progressive decrease of CD4+ T cells: There is continuous destruction of CD4+ T cells in the lymphoid tissue accompanied by a steady decrease in their number in the peripheral blood.
• Inversion of CD4+/CD8+ ratio: Normal CD4+/CD8+ ratio is 1:2. Loss of CD4+ cells in AIDS patient leads to inversion of ratio of 0.5 or less.
• HIV Infection of Non-T Cells: HIV can infect non-T cells such as macrophages and dendritic cells (mucosal and follicular).

Abnormalities of B-cell Function:

• Polyclonal activation of B cells → hypergammaglobulinemia → circulating immune complexes.
• Impaired humoral immunity → disseminated infections caused by capsulated bacteria, such as S. pneumoniae and H. influenza.

Natural History of HIV Infection:

The virus usually enters the body through mucosal epithelia and the clinical course can be divided into three main phases:

1. Early acute phase: It may present as an acute (refer to above), usually self-limited nonspecific illness. These symptoms include sore throat, myalgias, fever, weight loss, and fatigue.

• Other features, such as rash, cervical adenopathy, diarrhea, and vomiting, may also occur.
• Centers for Disease Control (CDC) classification of HIV infection: IT depends on blood
• CD4+ T-cell count. This divides the patients into three categories with the counts being:
• Greater than 500 cells/μL
• Between 200 to 500 cells/μL
• Less than 200 cells/μL.

2. Middle chronic phase: It may have few or no clinical manifestations, and is called the clinical latency period. The symptoms may be due to minor opportunistic infections, such as oral candidiasis (thrush), vaginal candidiasis, herpes zoster, and perhaps mycobacterial tuberculosis.

3. Final crisis phase: It is the final phase of HIV with progression to AIDS. It presents with fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and secondary neoplasms. Most of untreated (but not all) patients with HIV infection progress to AIDS after a chronic phase lasting from 7 to 10 years. The opportunistic infections and neoplasms found in patients with HIV infection are presented in Table.

Write briefly on common neoplasms in HIV patients.

AIDS-defining opportunistic infections and neoplasms found in patients with HIV infection:

Diagnosis of HIV Infection or AIDS:

1. ELISA: Detects antibodies against viral proteins. It is the most sensitive and best screening test for the diagnosis of AIDS.
2. Western blot: Most specific or the confirmatory test for HIV.
   • Direct detection of viral infection:
   • p24 antigen capture assay
   • Reverse transcriptase polymerase chain reaction (RT-PCR)
   • DNA-PCR
   • Culture of virus from the monocytes and CD4+T cells.
3. Prognosis: The prognosis of AIDS is poor.

Amyloidosis

Define amyloidosis.

Definition of Amyloidosis: Amyloid is a pathologic fibrillar protein deposited in the extracellular space in various tissues and organs of the body in a variety of clinical condition.

General Features of Amyloidosis:

• Associated with a number of inherited and inflammatory disorders.
• Extracellular deposits cause structural and functional damage to the involved tissue.
• Basically a disorder of protein misfolding and is produced by aggregation of misfolded proteins (normally folded proteins are soluble) or protein fragments.
• It also contains abundant charged sugar groups and has staining characteristics that were thought to resemble starch (amylose) and were called as amyloid. But these deposits are not related to starch.
• Usually a systemic (sometimes localized) disease.

Forms of Amyloidosis:

All amyloid have same morphological and staining property but amyloidosis is not a single disease. It is a group of diseases having in common the deposition of similar-appearing proteins in which biochemical structure (more than 20 different proteins) and mechanism of formation are different.

Physical Nature of Amyloid:

• All types of amyloid are composed of nonbranching fibrils of 7 to 10 nm diameter.
• Each firil consists ofβ-pleated sheet polypeptide chains and is wound around one another.
• Congo red dye binds to these girls and produces classic apple-green birefringence (dichromism). Hence, Congo red stain is used to identify amyloid deposits in tissues.

Chemical Nature of Amyloid:

Write a short note on the physical and chemical nature of amyloid.

Fibrillar proteins bind with a variety of substances:

• About 95% of the amyloid material consists of viral proteins.
• The remaining 5% consists of proteoglycans, glycosaminoglycans, serum amyloid P, etc.

Biochemical Forms of Amyloid:

It consists of three major distinct proteins and more than 20 minor forms.

1. Major forms: These are AL, AA, and Aβ amyloid

• AL (amyloid light chain) protein:
  • Consists of complete immunoglobulin (Ig) light chains or the aminoterminal fragments of light chains, or both.
  • Produced by plasma cells and associated with some monoclonal B cell proliferation
    (for example, Plasma cell tumors).
• AA (amyloid-associated) protein:
  • Non-immunoglobulin.
  • Derived from a larger precursor in the serum called SAA (serum amyloid-associated) protein synthesized by the liver. Increased synthesis of SAA protein occurs under the influence of cytokines( for example, IL-6 and IL-1) during inflammation.
  • Associated with chronic inflammation (called as secondary amyloidosis).
• Aβ amyloid:
  • Derived from transmembrane glycoprotein called amyloid precursor protein (APP).
  • Found in the cerebral lesions of Alzheimer’s disease.

2. Minor types:

• Transthyretin (TTR):
  • It is a normal serum protein that transports thyroxine and retinol.
  • Mutations in gene encoding TTR → alter its structure → misfolds.
  • Found in familial amyloid polyneuropathies, the heart of aged individuals (senile systemic amyloidosis).
• β₂-microglobulin:
  • It is a normal serum protein.
  • Amyloid firil subunit namely Aβ2m is derived from β2-microglobulin and is found in amyloidosis of patients on long-term hemodialysis.
• Other minor types:
  • Serum amyloid P component, proteoglycans, and highly sulfated glycosaminoglycans.
  • Pathogenesis of Amyloidosis
  • Write a short note on the pathogenesis of amyloidosis.
  • Misfolding of Proteins
  • Amyloidosis is a disorder due to abnormal folding or misfolding of proteins.

Pathogenesis of Amyloidosis:

 Write a short note on the pathogenesis of amyloidosis.

1. Misfolding of Proteins:

• Amyloidosis is a disorder due to abnormal folding or misfolding of proteins.
• Normally, misfolded proteins are degraded either intracellularly in proteasomes, or extracellularly by macrophages.
• In amyloidosis, there is a failure of control mechanism → production of misfolded proteins, which exceeds the degradation → accumulation outside cells. These misfolded proteins are unstable and self-associated → deposited as fibrils in extracellular tissues.

2. Categories of Proteins:

Misfolded proteins that form amyloid may be the result of:

Production of Abnormal Amounts of Normal Protein:

• These proteins have an inherent tendency to fold improperly or undergo misfolding → associate and form fibrils.
• Example: During inflammation, SAA is synthesized by the liver cells under the influence of cytokines such as IL-6 and IL-1 secreted by activated macrophages, and is degraded by monocyte-derived enzymes.
• In individuals prone to amyloidosis, there may be defects in the monocyte-derived enzymes → incomplete breakdown of SAA → formation of insoluble AA molecules. Genetically, defective SAA may also be responsible for resistant degradation by macrophages.

Production of Normal Amount of Mutant Protein:

• This protein is prone to misfolding and subsequent aggregation to form amyloid.
• Example: In familial amyloidosis, mutation of gene encoding TTR → alterations in structure serum protein TTR → proteins prone to misfolding → aggregate → are resistant to proteolysis.

Pathological Effects:

• Pressure on adjacent normal cells → leads to atrophy of cells.
• Deposition in the blood vessel wall causes:
• Narrowing of the lumen → leads to ischemic damage.
• Increased permeability → escape of protein out of the vessel.

Classification of Amyloidosis:

Classify amyloidosis.

Amyloidosis is classified depending on biochemical and clinical characteristics .

Classification of amyloidosis:

1. Systemic (Generalized):

It involves several organ systems.

1. Primary Amyloidosis:

Describe the pathology of primary amyloidosis.

Immunocyte Dyscrasias with Amyloidosis:

• Usually systemic and is of AL type.
• Many have underlying plasma cell dyscrasia, for example, Multiple myeloma.

Multiple myeloma:

• About 5% to 15% of patients develop amyloidosis.
• Tumors synthesize abnormal amounts of a single specific Ig (monoclonal gammopathy)
• appears as an M (myeloma) protein spike on serum electrophoresis.
• The tumor also synthesizes the light chains (known as Bence-Jones protein) of either the κ or the λ type which are found in the serum.
• Bence-Jones protein being of small molecular size can be excreted in the urine. The amyloid deposits in these patients contain the same light chain protein.

Primary amyloidosis without plasma cell dyscrasia:

• The majority of patients with AL amyloid do not have multiple myeloma or any other overt
  plasma cell neoplasm.
• But almost all these patients have monoclonal immunoglobulins or free light chains, or both, in the serum or urine.
• Bone marrow in most show an increase in the number of plasma cells, which may secrete the precursors of AL protein. Thus, these may represent plasma cell dyscrasia characterized by the production of an abnormal protein, instead of the production of tumor masses.

2. Reactive Systemic (Secondary) Amyloidosis:

Write a short note on reactive systemic amyloidosis.

• Systemic in distribution and is of AA type.
• Occurs as a complication of (secondary to) chronic inflammatory or tissue-destructive process. Hence, was known as secondary amyloidosis.
• Complicates or occurs in association with diseases, such as:
  1. Chronic inflammatory conditions: For example, Tuberculosis, bronchiectasis, and chronic osteomyelitis.
  2. Autoimmune states: For example, Rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis).
  3. Heroin abusers: These patients develop chronic skin infections or abscesses due t subcutaneous self-administration of narcotics.
  4. Nonimmunocyte-derived tumors: For example, Renal cell carcinoma and Hodgkin lymphoma.

3. Hemodialysis-associated Amyloidosis:

Patients with chronic renal failure on long-term hemodialysis have high levels of β2- microglobulin in the serum because it cannot be fitered through dialysis membranes → gets deposited as amyloid.

2. Hereditary or Familial Amyloidosis

It constitutes a heterogeneous group, are rare and occur in certain geographic areas.

Familial Mediterranean Fever:

• Autosomal recessive disorder.
• Characterized by recurrent attacks of fever accompanied with inflammation of serosal
  surfaces (peritoneum, pleura, and synovial membrane).
• The gene encodes a protein called pyrin (for its relation to fever), which regulates inflammatory reactions by producing high levels of proinflammatory cytokines IL-1.
• The amyloid fibril proteins are of AA type probably produced due to recurrent bouts of
  inflammation.

Familial Amyloidotic Neuropathies:

It is characterized by the deposition of amyloid in peripheral and autonomic nerves and the fibrils are made up of mutant TTRs.

3. Localized Amyloidosis:

• Amyloid deposits are limited to a single organ (For example, Heart) or tissue.
• Either grossly visible as nodular masses or detected only by microscopic examination.
• Sites: Lung, larynx, skin, urinary bladder, and tongue.
• Microscopy: Amyloid deposits may be surrounded by lymphocytes and plasma cells.

Endocrine Amyloid:

• Endocrine tumors such as medullary carcinoma of the thyroid, islet tumors of the pancreas, pheochromocytomas, and undifferentiated carcinomas of the stomach.
• Islets of Langerhans in type II diabetes mellitus.

Amyloid of Aging:

• Senile systemic amyloidosis is characterized by the systemic deposition of amyloid in elderly patients usually between 70 to 80 years.
• Also called senile cardiac amyloidosis because of the symptoms related to restrictive cardiomyopathy and arrhythmias.
• The amyloid is composed of the normal TTR molecule.

Write short notes on special stains for amyloid.

Morphology of special stains for amyloid:

• Main Organs Involved:
  • Secondary amyloidosis: Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid.
  • Primary amyloidosis: Heart, GI tract, respiratory tract, peripheral nerves, skin, and tongue.
• Gross:
  • May or may not be apparent grossly.
  • If a large amount accumulates → affected organs are enlarged, firm, and have a waxy appearance.
  • Cut surface: If the amyloid deposits are large, painting the cut surface with iodine gives a yellow color, which is transformed to blue violet after the application of sulfuric acid (which acidifies iodine).
  • This method was used for demonstrating cellulose or starch. This staining property was responsible for the coining of the term amyloid (starch-like). But it is neither starch nor cellulose.

Microscopy of special stains for amyloid:

• Hematoxylin and Eosin Stain:
  • Amyloid deposits are always extracellular and begin between the cells. In AL form perivascular and vascular deposits are common.
  • Progressive accumulation of amyloid produces pressure atrophy of adjacent cells.
  • Appears as an amorphous, eosinophilic, hyaline, glassy, extracellular substance.
  • Many other substances (e.g. collagen, fibrin) also stain eosinophilic with hematoxylin and eosin. Hence, it is necessary to differentiate amyloid from these other hyaline deposits by using special stains.

Staining (Tinctorial) Properties of Amyloid:

1. Congo red stain: It is the special stain used for the diagnosis of amyloidosis. Amyloid stains pink or red with the Congo red dye under ordinary light.
2. Van Gieson stains: It takes up the khaki color.
3. Alcian blue: It imparts a blue color to glycosaminoglycans in amyloid.
4. Periodic acid Schiff reaction (PAS): It stains pink.
5. Methyl violet and cresyl violet: These metachromatic stains give rose pink color.
6. Thioflavin T: It is not specific for amyloid, but amyloid gives fluorescence when viewed in ultraviolet light.
7. Immunohistochemical staining: It can distinguish AA, AL, and ATTR types.

Morphology of Major Organs Involved:

Kidney:

Kidney involvement is the most common and the most serious form of organ involvement.

• Gross: It may be of normal size and color during early stages. In advanced stages, it may be shrunken due to ischemia, which is caused by vascular narrowing induced by the amyloid deposit within arterial and arteriolar walls.
• Microscopy: Most commonly renal amyloid is of light-chain (AL) or AA type.
• Glomeruli: It is the main site of amyloid deposition.
  • First, focal deposits within the mesangial matrix, are accompanied by diffuse or nodular thickening of the glomerular basement membranes.
  • Later, both the mesangial and basement membrane deposits cause capillary narrowing. Progressive accumulation of amyloid results in obliteration of the capillary lumen and glomerulus shows broad ribbons of amyloid.
• Amyloid may also be deposited in the peritubular interstitial tissue, arteries, and arterioles.

Describe the gross and microscopic appearance of the spleen in amyloid (Sago and Lardaceous spleen).

Spleen:

• Gross: It may be normal in size or may cause moderate to marked splenomegaly (200–800g). It may show one of two patterns of deposition.
  • Sago spleen: Amyloid deposits are limited to the splenic follicles, which grossly appear like tapioca/sago granules; hence known as sago spleen. Microscopically, the amyloid is deposited in the wall of arterioles in the white pulp.
  • Lardaceous spleen: Amyloid is deposited in the walls of the splenic sinuses and connective tissue framework in the red pulp. This may result in moderate to marked enlargement of the spleen.
  • Fusion of the early deposits gives rise to large, maplike areas of reddish color on the cut surface. This resembles pig fat (lardaceous) and is hence called as lardaceous spleen. Microscopically, it shows amyloid deposits in the wall of the sinuses.
• Light microscopy: These deposits appear homogenous pink, which when stained with Congo red and viewed under a polarizing microscope, give rise to characteristic green birefringence.

Clinical Features  of the spleen in amyloid:

• Amyloidosis may not produce any clinical manifestations, or it may produce symptoms related to the sites or organs affected.
• Clinical manifestations initially may be nonspecific (for example, Weakness, Weight loss). Specific symptoms appear later and are related to renal, cardiac, and gastrointestinal involvement.
• Renal involvement: It gives rise to proteinuria sometime massive enough to cause nephrotic syndrome. In advanced cases, the obliteration of glomeruli causes renal failure and uremia.