Immunopathology Including Amyloidosis

Normal Immune System

Immunity may be defined as normal body defense mechanism from invading infectious agents and plays a limited role in launching an attack against cancer.

A critical balanced state of the immune system is essential for the human body because deranged immune responses (excess, absence, abnormal, inappropriate) may all lead to major diseases of the immune system:

Read And Learn More  Amyloidosis

• Immunodeficiency disorders:  Are characterized by deficient or absent cellular and/or humoral immune functions. This group is comprised by a list of primary and secondary immunodeficiency diseases (including acquired immunodeficiency syndrome AIDS).
• Hypersensitivity reactions:  Are characterized by hyperfunction or inappropriate response of the immune system and cover the various mechanisms of immunologic tissue injury.
• Autoimmune diseases:  Occur when the immune system fails to recognise ‘self’ from ‘nonself’. A growing number of autoimmune and collagen diseases are included in this group.
• Possible immune disorders:  In which the immunologic mechanisms are suspected in their etiopathogenesis.

A classical example of this group is amyloidosis. However, the pathogenesis of diseases of immunity is best understood after reviewing and recalling the normal immune system; a brief overview on this has been done below which includes types of normal immunity, organs and cells of the immune system, and cytokines expressed by immune cells as immunomodulatory molecules.

Types of immunity:

Immunity is divided into 2 types

1. Natural (innate) and
2. Specific (adaptive)

Both of these are interrelated in their function, Normal Immune (adaptive), both of which are interrelated in their function:

Natural (Innate) Immunity:

The innate immune response is inborn and is the first line of defense against pathogens. It has following features:

• It lacks antigenic specificity i.e. it is non-specific.
• It is a rapid response appearing within minutes.
• It has no memory and thus does not confer long-lasting immunity to the host.

Components of Innate Immunity:

Innate immunity has four components: epithelial barriers, cellular defenses, soluble mediators, and pattern recognition receptors, discussed below.

1. Epithelial barriers:  The surface of the skin and mucous membranes (for example, the Oral cavity, GI tract, and respiratory tract) provide natural mechanical barriers to the invading microorganisms.

2. Cellular defenses: These include the following:

• Neutrophils make their appearance first at the site of infection within a short time.
• Macrophages are scavenger cells that are rapidly recruited from circulating monocytes.
• Dendritic cells are a special type of marrow-derived cells present in the lymphoid tissues, skin (where these are called Langerhans cells), nose, lungs, GI tract etc. Unlike macrophages, these cells are not phagocyte for the microbial agent but instead, they take up, process, and present antigens to T-lymphocytes.
• Natural killer (NK) cells are effector lymphocytes and play a major role in the elimination of virally-infected cells and tumor cells (i.e. cytotoxic lymphocytes).
• Mast cells are bone marrow-derived cells that migrate and mature in the various connective tissues of the body. Morphologically similar to basophils, mast cells produce various inflammatory mediators and are considered master regulators of the immune system.

Innate lymphoid cells are a small subgroup of lymphocytes that mediate innate immunity by elaboration of certain cytokines (IL-5, IL-17, IL-22, IF-γ). They are different than other T lymphocytes in lacking TCRs.

3. Soluble mediators:  Several soluble proteins play an important role in innate immunity:

• Kinin derived from the kinin-kallikrein system has pro-inflammatory functions.
• Complements are plasma proteins that are activated by invading microbes in innate immune response using the alternate pathway of activation.
• C-reactive protein is a liver-derived acute-phase reactant protein and its levels rise in response to inflammation. It coats the microbes and promotes phagocytosis.
• Mannose-binding lectin is a liver-derived protein that performs a role in innate immunity by recognizing molecular patterns of microbes to distinguish them from self.
• Surfactant coating the respiratory passages provides protection against inhaled microbial agents.

4. Pattern-recognition receptors: 

While invading organisms and dead cells have certain molecular patterns termed pathogen-associated molecular patterns (PAMPs), cells other than lymphoid cells participate in innate.

Immunity (epithelial cells, macrophages, dendritic cells) possess pattern-recognition receptors which are present in various components of the participating cells (i.e. on the plasma membrane, cytosol, or on endoscopes which are membrane-bound intracellular vesicles formed by endocytosis).

Accordingly, the following 4 major types of pattern-recognition receptors have been described:

1. Toll-like receptors (TLRs):

Are the most important receptors for pattern recognition of microbial molecules and these are located on the cytoplasmic membrane and endosomal vesicles of the participating cell. There are over 10 types of TLRs, each with a distinct function; TLR4 recognises lipopolysaccharides (LPS) on gram-negative bacteria. TLRs act by expression of certain pro-inflammatory cytokines which recruit and activate leucocytes.

2. NOD-like receptors (NLRs):

A re-dispersed in the cytosol (NOD stands for nucleotide oligomerization domain-like). NLRs play several diverse roles:

• Recognition of microbial products
• Recognition of products of dead cells
• Recognition of biochemical changes in cell metabolism during cell injury Mode of action of NLRs is not quite clear. In microbial infection.
• NLRs interact with another group of cytosolic protein complexes called inflammasomes which directly activate caspase-1.
• Activated caspase-1 secretes proinflammatory cytokines and induces cell death by pyroptosis .
• RIG-like receptors (RLRs) are also cytosolic and specifically target viral nucleic acids inside the infected host cells by expression of anti-viral cytokines.
• C-type lectin receptors (CLRs) are expressed on the plasma membrane of macrophages and dendritic cells of innate immunity. CLRs have specificity for inciting inflammatory reaction against fungal infection.

Besides these 4 major categories of receptors, a few others are mannose receptors (which identify bacterial sugars) and G-protein-associated receptors located on leucocytes (which identify bacterial peptides).

Functions of pattern recognition proteins, TLRs, NLRs, and RLRs, provide the main point of connection between innate and adaptive immunity, eventually resulting in intracellular events that lead to microbial killing and further recruitment of immunocompetent T and B cells.

Major Functions of Innate Immunity

Innate immunity is inborn but it lacks memory. It plays the following major roles in the human body:

• Initial inflammatory reaction:  By the body in response to invading microorganisms by neutrophils and macrophages which is due to activation of innate immunity.
• The antiviral role played:  by cytokines expressed by activated innate immunity when host cells are infected with viruses.
• Initiation and subsequent direction of adaptive immune response: Is determined by activation of specialized antigen-presenting cells (i.e. dendritic cells) for presentation to T lymphocytes for specific immunity.

2. Specific (Adaptive) Immunity:

• Specific or adaptive immunity is directed specifically against an invading pathogen. The specific immune response is elicited by two major classes of lymphocytes, and accordingly two types of immune responses:
• T lymphocytes have diverse receptors for various substances (or antigens); this is termed cellular immunity.
• B lymphocytes secrete immunoglobulins (or antibodies); this is called humoral immunity.

Further details of various classes of lymphocytes and their functions are discussed under ‘cells of the immune system’.

Major Functions of Adaptive Immunity:

The functions of adaptive immunity are related to effector and memory response by the participating cells:

• Recognition of self from non-self antigen, followed by the presentation of non-self to lymphocytes.
•  Mount a specific response against the non-self agent and eliminate the agent of the infected cell.
• Development of immunological memory in which pathogen is remembered through memory cells.
• Secretion of immunoglobulins by B lymphocytes and plasma cells which act as antibodies against antigenic substances.

Salient contrasting features of innate and adaptive immunity are outlined in Table

Contrasting features of innate and adaptive immunity:

Types of Immunity;

• Immunity is normal body defenses against pathogens, and to a limited extent against cancer.
• Immunity is divided into 2 types, natural (innate) and specific (adaptive); each has humoral and cellular components.
• Innate immunity is inborn and is the first line of defense against pathogens but lacks memory.
• It has four components: epithelial barriers, cellular defenses, soluble mediators, and pattern recognition receptors. Its major functions are initial inflammatory reaction, antiviral action, and initiation of the subsequent direction of the adaptive immune response.
• Adaptive or specific immunity is directed specifically against an invading pathogen and has memory.
• It is elicited by two sets of lymphocytes, each with anti-microbial effector action and immunologic memory function:
• T lymphocytes and their subtypes having diverse surface receptors mediate cellular immunity, and B lymphocytes which secrete immunoglobulins (or antibodies) mediate humoral immunity.