IMMUNE SYSTEM

Adaptive Immune system deficiencies

Immunity against specific infectious agents

Aided by the actions of the innate system and primarily acts on infections by recognitions of “Non-self” from “self” antigens.

Is the basis of effective immunization against infectious diseases

The cells of the adaptive immune system include:

Antigen-specific T cells: which are activated to proliferate through the action of APCs

B cells which differentiate into plasma cells to produce antibodies.

Antibody deficiencies are defined by a loss of immunoglobulins or failure of immunoglobulin function, resulting in increased susceptibility to infection.

In primary deficiencies: Inherited or sporadic genetic mutation(s), in some cases with unknown environmental cofactors, are suspected with no other known cause. Usually, rare.

Secondary antibody deficiency: Occurs as a consequence of other diseases or medications. Studies describe secondary antibody deficiencies as a result of haematological malignancy, immunosuppressive or anti-convulsant medications, protein-losing enteropathy, nephrotic syndrome and trauma.

Antibody deficiencies are defined by a loss of immunoglobulins or failure of immunoglobulin function, resulting in increased susceptibility to infection.

In primary deficiencies: Inherited or sporadic genetic mutation(s), in some cases with unknown environmental cofactors, are suspected with no other known cause. Usually, rare.

Secondary antibody deficiency: Occurs as a consequence of other diseases or medications. Studies describe secondary antibody deficiencies as a result of haematological malignancy, immunosuppressive or anti-convulsant medications, protein-losing enteropathy, nephrotic syndrome and trauma.

Etiology:

Results from mutation of the Bruton's tyrosine kinase gene (Btk) located on the long arm (q) of the X chromosome (Xq21.3-Xq22), affecting males almost exclusively.

Pathophysiology:

The gene for Btk codes for a cytoplasmic tyrosine kinase protein, BTK, which acts as a signal transducer driving the final stages of B cell maturation.

The inheritance of disease-causing mutation of the Btk gene interferes with BTK protein expression, resulting in the arrest of differentiation at the pre-B-cell stage in the bone marrow, causing a profound lack of mature B lymphocytes in the peripheral circulation and a corresponding absence or severe reduction in all immunoglobulin isotypes from the serum.

Diagnosis of X-linked agammaglobulinemia is by detecting low (at least 2 standard deviations below the mean) levels of immunoglobulins (IgG, IgA, IgM) and absent B cells (< 1% of all lymphocytes are CD19+ cells, detected by flow cytometry). Transient neutropenia may also be present.

Genetic testing can be used to confirm a diagnosis but is not required. It is usually recommended for 1st-degree relatives. If the mutation has been identified in family members, mutational analysis of chorionic villus, amniocentesis, or percutaneous umbilical cord blood samples can provide prenatal diagnosis.

Treatments: Immune globulin replacement therapy

Treatment of X-linked agammaglobulinemia is immune globulin replacement therapy.

Prompt use of adequate antibiotics for each infection is crucial; bronchiectasis may require frequent rotation of antibiotics. Live-virus vaccines are contraindicated.

Hyperimmunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.

Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease.

Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches.

The major concerning gene to be mutated is CD40 ligand (CD40L) gene whereas several other genes are also found to effect pathogenies.

CD40 ligand expression and genetic testing

Diagnosis of hyper-IgM syndrome is suspected based on clinical criteria, including recurrent sinopulmonary infections, chronic diarrhea, and lymphoid hyperplasia. Serum Ig levels are measured; normal or elevated serum IgM levels and low levels or absence of other immunoglobulins support the diagnosis. Flow cytometry testing of CD40 ligand expression on T-cell surfaces should be done.

When possible, the diagnosis is confirmed by genetic testing. Prenatal genetic testing can be offered to women considering pregnancy if they have a family history of CD40 ligand deficiency. Genetic testing of other relatives is not routinely done.

Other laboratory findings include a reduced number of memory B cells (CD27) and absence of class-switched memory B cells (IgD-CD27).