Immunodeficiency Diseases Symptoms And Causes Notes

Immunodeficiency Diseases

Failure or deficiency of the immune system, which normally plays a protective role against infections, manifests by occurrence of repeated infections in an individual having immunodeficiency.

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Failure in immunity may be in innate or adaptive; inherited or acquired; humoral (B-cell related) or cell-mediated (T-cell mediated).

Traditionally, immunodeficiency diseases are classified into 2 groups:

• Primary (or congenital) immunodeficiency diseases (PIDs) are the result of genetic or developmental abnormality of the immune system.
• Secondary (or acquired) immunodeficiency arise from acquired suppression of the immune system.

Although the most important example of this group is acquired immunodeficiency syndrome (AIDS) caused by HIV and presenting with certain constitutional features

Immunodeficiency may also result from the following acquired causes:

• Cancers on chemotherapy, radiotherapy.
• Lymphoid neoplasms, for example, Lymphomas, lymphoid leukaemia Severe malnutrition
• Autoimmune diseases on disease-modifying drugs, for example, Sarcoidosis Post-transplant cases on immunosuppressive therapy

However, in the following pages, after a brief account of PIDs, a detailed discussion on Aids follows.

Primary Immunodeficiency Diseases

• Primary immunodeficiency diseases (PIDs) are genetically determined or congenital diseases.
• Since the first description of a PID was made by Bruton in 1952, over 250 PIDs with a variety of mutations have been described. Overall incidence of PIDs is approximately 5 per 100,000 persons.
• PIDs may involve any component of immunity (innate or adaptive, B or T cells); accordingly, a short list of common PIDs is given in table. Brief comments on some common PIDs is given below.

Bruton’S Disease:

Also called X-linked agammaglobulinemia, this is more common form of PID. Its salient features are as under:

• It is a disorder of failure of B cell precursors (pre-B) to develop into mature B cells due to mutation in the BTK (Bruton tyrosine kinase) gene located on the X-chromosome.
• The result is the absence of γ-globulin synthesis, and hence agammaglobulinaemia.
• The disease occurs almost exclusively in male children, manifesting by about 6 months of age, by which time maternally-acquired immunoglobulins are depleted.
• Patients commonly manifest with recurrent bacterial respiratory tract infections, viral infections of the GI tract, protozoal infection with Guardian etc.
• However, T cell immune functions are well-preserved and retained.
• Autoimmune disease association is seen in about a quarter of cases.

Digeorge’S Syndrome:

This is due to developmental hypoplasia of the thymus from deletion in the long arm of chromosome 22. Its salient features are:

• Severe T cell defect due to failure in embryologic development of thymus.
• Often accompanied with other developmental defects; CHARGE syndrome may be associated (coloboma of eye, heart anomaly, choanal atresia, retardation, genital and ear anomalies).

Classification of primary immunodeficiency diseases (PIDs):

• Patients have very low T cells in blood and lymphoid organs, and hence poor defence again infections.

Common Variable Immunodeficiency

• This is a heterogeneous group of conditions due to inherited or sporadic patterns of impaired B cell function, with or without actual fall in count of B cells and plasma cells.
• Thus, there is impaired antibody production resulting in low levels of all immunoglobulins, in particular IgG; hypogammaglobulinaemia is common.

Clinical features may be:

• Splenomegaly
• Antibody-mediated autoimmune lesions
• Granulomatous lesions and colitis
• Malignant lymphomas

Selective Iga Deficiency:

This is the most common type of PID; incidence being 1 in every 600 individuals. Underlying genetic defect is similar to common variable immunodeficiency but selectively affects IgA-producing B cells and plasma cells. Most patients are asymptomatic; others may have the following manifestations:

• Frequent respiratory infections
• Bronchiectasis
• Susceptibility to drug allergies
• Autoimmune diseases

Hyper-Igm Syndromes

This is a rare B cell PID in which there is a defect in IgM synthesis resulting in normal or high levels of IgM accompanied with very low levels of IgG, IgA adn IgE.

The underlying defect is either an autosomal recessive deficiency of CD40 molecule or X-linked CD40L (also called CD154), affecting the function of CD4+ helper T cells and consequently B cell dysfunction.

• T and B cells count, however, remains normal. Clinical features are:
• Recurrent infections
• Pneumocystis pneumonia
• Autoimmune haemolytic anaemia

Serve Combined Immune Deficiency(SCID):  Has syndromic features due to defects in humoral (B cells), cell-mediated (T cell) and NK cell immune functions.

SCID may have X-linked or autosomal recessive inheritance, both forms having features of depleted lymphoid cells in the thymus:

• X-linked SCID: Is seen in boys and is more common. The defect lies in inherited mutation in γ-chain cytokine receptor on lymphoid precursor cells, leading to failure of cytokine (IL-7) signal-transduction pathway. Since cytokine IL-7 is required for proliferation and survival of lymphoid precursors, the outcome is the failure of functioning mature T, B and NK cells, hence combined immunodeficiency.
• Autosomal recessive SCID: Is less common. It is due to deficiency of the enzyme, adenosine deaminase (ADA) from JAK3 mutation, leading to intracellular accumulation of toxic intermediate metabolites in the immature lymphoid cells, hence hampering functioning population of B and T cells.

Wiskott-Aldrich Syndrome (WAS)

This is an uncommon recessive X-linked disease caused by mutation in WASP gene that affects T cells, dendritic cells and platelets.

• Typically, WAS has the following features:
• Recurrent bacterial infections
• Eczema
• Thrombocytopenia and bleeding tendencies

Ataxia Telangiectasia (AT)

This is an autosomal recessive disorder having a mutation in the gene coding for ATM protein (AT Mutated), a kinase that plays an important role in the detection and repair of DNA.

AT has a combination of features of abnormality in gait (cerebellar ataxia), malformed blood vessels (telangiectasia), higher incidence of some malignancies (lymphoma, leukemia, childhood carcinomas) and immunodeficiency. Immune dysfunction causes B cell defect (low level of IgA, deficiency of IgG2, low antibody production) and progressive T cell immune deterioration.

Primary Immunodeficiency Diseases (PIDs):

Immunodeficiency diseases manifest by the occurrence of repeated infections.

• Failure in immunity may be in innate or adaptive; inherited (primary) or acquired (secondary); humoral (B-cell related) or cell-mediated (T-cell mediated).
• PIDs are genetically determined or congenital diseases and as a group are less common.
• Bruton’s disease is the first described PID, is more common and is an X-linked agammaglobulinaemia, a B cell disorder.
• Di George’s disease is due to congenital thymic hyperplasia and is a severe T-cell defect.
• Common variable immunodeficiency is a heterogeneous disorder of B cells and plasma cells having hypogammaglobulinaemia.
• Selective IgA deficiency is the most common PID and has isolated defects in IgA-producing B cells and plasma cells.
• Hyper-IgM syndrome is a rare B cell disorder with defects in IgM synthesis with high levels of IgM and very low levels of other immunoglobulins.
• Severe combined immunodeficiency has defect in B, T and NK cells, having X-linked or autosomal recessive inheritance.
• Wiskott-Aldrich syndrome is an X-linked disease affecting platelets, dendritic cells and T cells.
• Ataxia telangiectasia is a defect in DNA repair and presents with an abnormal gait, malformed vessels and predisposition to certain cancers.