Immunodeficiency disorders

They may involve T cell, B cell, combined, phagocytic and complement deficiencies. Patients with T cell disorders will primarily have recurrent viral, fungal and intracellular bacterial infections. They will be at increased risk of malignancies. Patients with B cell disorders will present with recurrent bacterial infections especially with capsulated bacteria like Pneumococci and H.influenzae. Patients with complement or phagocytic deficiencies will also present with recurrent pyogenic infections.

Deficiency primarily of humoral immunity

1. Selective IgA immunodeficiency: It is the most common primary immunodeficiency. Individuals with this condition have a complete absence or severe deficiency of IgA, which is essential in the respiratory and gastrointestinal tracts. Other types of immunoglobulins are present in normal amounts. Some patients may have low levels of IgG2 and IgG4. They are prone to allergies, respiratory, gastrointestinal and mucosal infections, diarrhea and autoimmune diseases. Many patients may appear normal and have relatively mild disease. Patients with IgA deficiency should not be treated with immunoglobulins or given blood transfusions for risk of allergic reactions and depletion of already low levels of Ig A.
2. Common variable immunodeficiency: It is caused by defects in B cell function from deficiency of two or more immunoglobulins like IgG and IgA or IgM. They show a poor response to vaccination with measles and influenza vaccines. Few individuals show a mutation in the TNFRSF13B gene that affects survival and maturation of B cells. Patients present with recurrent bacterial infections of the lungs, sinuses, GI tract and ears like pneumonia, diarrhea and weight loss. Lymphadenopathy and splenomegaly are seen. Autoimmune disorders are seen more commonly like rheumatoid arthritis, autoimmune thrombocytopenia and hemolytic anemia. There is increased risk of non-Hodgkin lymphoma and gastric cancer.
3. Hyper IgM syndrome: It is an AR or X linked recessive disorder caused by mutations in gene encoding CD 40 Ligand (CD40LG) in CD4 Helper T cells due to which the interaction between CD 40 on B cells and CD 40 ligand on T cells does not happen, which blocks class switching from IgM to other types of Igs. High conc of Ig M but low Ig G, A and E. Normal numbers of T and B cells are seen, neutropenia may occur in some cases. Individuals present with frequent infections like pneumonia, sinusitis, otitis, chronic diarrhea and failure to thrive. They may develop autoimmune disorders, CNS infections and lymphomas.
4. ** X-linked or Bruton’s agammaglobulinemia (XLA): **It is an X linked immunodeficiency caused by mutations in the BTK (Bruton’s tyrosine kinase) gene that causes a block in B cell development and lack of antibodies. Infants with XLA are protected during the first two months of life due to the presence of maternally transferred antibodies. After this time, they develop recurrent bacterial infections like pneumonia, bronchitis, otitis, conjunctivitis, sinusitis and chronic diarrhea. B cells are very low or absent and immunoglobulin numbers are also low.

Deficiency primarily of cell-mediated immunity

1. Wiskott Aldrich Syndrome: It is an X linked recessive disorder caused by a mutation in the WAS gene that encodes a protein called WASP that is involved in relaying signals from the surface of blood cells to the actin cytoskeleton. It affects cellular mobility and adhesion. IgG and IgA levels are normal. CMI is variable. Microplatelets are seen. There are recurrent pyogenic, viral and fungal infections, eczema and bleeding due to thrombocytopenia. There is increased risk of autoimmune disorders like RA, vasculitis and hemolytic anemia.
2. DiGeorge syndrome or thymic aplasia or velocardiofacial syndrome: In Thymic Aplasia, both thymus and parathyroids fail to develop normally as a result of defect in third and fourth pharyngeal pouches. It is caused by a deletion on chromosome 22q, inherited as AD. Risk factors include maternal DM, exposure to alcohol and retinoic acids. It presents with cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia (CATCH 22). Characteristic facial features include low set ears, wide set eyes, small jaw and short groove in the upper lip. Other abnormalities include recurrent infections, high arched palate, bifid uvula, hearing loss, skeletal defects, learning disabilities, ADHD and autism spectrum disorder.
3. Chronic mucocutaneous candidiasis: Chronic mucocutaneous candidiasis refers to a group of heterogeneous disorders characterized by persistent, debilitating and/or recurrent infections of the skin, nails and mucus membranes, mainly with the fungal pathogen Candida albicans. It may be associated with Di George syndrome and is seen with inherited or acquired T cell deficiencies.
4. Job’s Syndrome (Hyper IgE syndrome): It is inherited as AD or a more severe AR form. It presents with recurrent cold abscesses, eczema, skeletal defects and high levels of IgE. Defect is the failure to produce gamma interferon by helper T cells, which reduces the ability of macrophages to kill bacteria. Th2 response is increased. Severe, refractory molluscum contagiosum and sepsis can occur.

Combined deficiency of cell-mediated and humoral immunities

1. Severe combined immunodeficiency disease (SCID): It is a group of disorders which affect both cell mediated and humoral immunity. Patients typically present 2-6 months after birth with severe infections and rash, diarrhea, failure to thrive, severe diaper rash, measles, chicken pox, otitis, pneumonia, meningitis etc. Immunoglobulin levels are low, and tonsils and lymph nodes are absent. Live vaccines are contraindicated in SCID. It may be inherited as an AR or X linked disorder. Common causes of SCID include defect in gamma chain of IL 2 receptor (X linked), mutations in tyrosine kinase ZAP 70 gene, mutations in Janus Kinase 3, RAG 1 or 2 recombinase enzyme mutations (called Omenn Syndrome presenting with erythroderma, skin peeling, eosinophilia and increased IgE), adenosine deaminase or ADA and PNP deficiency. In SCID caused by deficiency of ADA or Purine Nucleoside Phosphorylase (PNP) there is an accumulation of d ATP, an inhibitor of ribonucleotide reductase and a decrease in deoxynucleoside triphosphate precursors of DNA. This reduces the formation of B cell and T cell precursors.

Bare Lymphocyte Syndrome is a type of SCID in which patients have defective Class I and/or II MHC. It is caused by mutations that affect the ability to synthesize a transcription factor required for the synthesis of the mRNA for MHC II proteins or mutations in TAP protein for MHC I.

Low levels of TREC or T cell receptor excision circles is used to diagnose SCID in newborn screening. Hematopoietic stem cell transplantation, ideally from a sibling, is the standard treatment for infants with SCID. Children who have SCID with ADA deficiency can be treated with enzyme replacement therapy called PEG-ADA. Gene therapy can be an effective treatment for some types of SCID, including X-linked SCID.