Immunodeficiency disorders

Immunodeficiency diseases may involve deficiencies of T cells, B cells, both (combined), phagocytes, or complement.

T cell disorders mainly cause recurrent viral, fungal, and intracellular bacterial infections, and they increase the risk of malignancy.
B cell disorders mainly cause recurrent bacterial infections, especially with encapsulated bacteria such as Pneumococci and H. influenzae.
Complement or phagocytic deficiencies also commonly present with recurrent pyogenic infections.

Deficiency primarily of humoral immunity

Selective IgA immunodeficiency: This is the most common primary immunodeficiency. Individuals have a complete absence or severe deficiency of IgA, which is important for immune defense in the respiratory and gastrointestinal tracts. Other immunoglobulins are present in normal amounts, although some patients may have low levels of IgG2 and IgG4. Patients are prone to allergies, respiratory, gastrointestinal, and mucosal infections, diarrhea, and autoimmune diseases. Many patients appear normal and have relatively mild disease. Patients with IgA deficiency should not be treated with immunoglobulins or given blood transfusions because of the risk of allergic reactions and depletion of already low levels of IgA.
Common variable immunodeficiency: This is caused by defects in B cell function, leading to deficiency of two or more immunoglobulins (such as IgG and IgA or IgM). Patients show a poor response to vaccination with measles and influenza vaccines. Some individuals have 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 (for example, pneumonia), along with diarrhea and weight loss. Lymphadenopathy and splenomegaly may be present. Autoimmune disorders are more common, including rheumatoid arthritis, autoimmune thrombocytopenia, and hemolytic anemia. There is an increased risk of non-Hodgkin lymphoma and gastric cancer.
Hyper IgM syndrome: This is an AR or X-linked recessive disorder caused by mutations in the gene encoding CD40 ligand (CD40LG) in CD4 helper T cells. As a result, the interaction between CD40 on B cells and CD40 ligand on T cells does not occur, which blocks class switching from IgM to other immunoglobulin types. Patients have a high concentration of IgM but low IgG, IgA, and IgE. T and B cell numbers are normal, and neutropenia may occur in some cases. Individuals present with frequent infections such as pneumonia, sinusitis, otitis, chronic diarrhea, and failure to thrive. They may develop autoimmune disorders, CNS infections, and lymphomas.
X-linked or Bruton’s agammaglobulinemia (XLA): This is an X-linked immunodeficiency caused by mutations in the BTK (Bruton’s tyrosine kinase) gene, leading to a block in B cell development and a lack of antibodies. Infants with XLA are protected during the first two months of life due to maternally transferred antibodies. After this period, they develop recurrent bacterial infections such as pneumonia, bronchitis, otitis, conjunctivitis, sinusitis, and chronic diarrhea. B cells are very low or absent, and immunoglobulin levels are also low.

Deficiency primarily of cell-mediated immunity

Wiskott Aldrich Syndrome: This is an X-linked recessive disorder caused by a mutation in the WAS gene, which encodes WASP. WASP relays signals from the surface of blood cells to the actin cytoskeleton, affecting cellular mobility and adhesion. IgG and IgA levels are normal, and cell-mediated immunity (CMI) is variable. Microplatelets are seen. Patients have recurrent pyogenic, viral, and fungal infections, eczema, and bleeding due to thrombocytopenia. There is an increased risk of autoimmune disorders such as rheumatoid arthritis, vasculitis, and hemolytic anemia.
DiGeorge syndrome or thymic aplasia or velocardiofacial syndrome: In thymic aplasia, both the thymus and parathyroids fail to develop normally due to a defect in the third and fourth pharyngeal pouches. It is caused by a deletion on chromosome 22q and is inherited as AD. Risk factors include maternal DM and 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, a small jaw, and a 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.
Chronic mucocutaneous candidiasis: This refers to a group of heterogeneous disorders characterized by persistent, debilitating, and/or recurrent infections of the skin, nails, and mucous membranes, mainly with the fungal pathogen Candida albicans. It may be associated with DiGeorge syndrome and is seen with inherited or acquired T cell deficiencies.
Job’s Syndrome (Hyper IgE syndrome): This is inherited as AD, with a more severe AR form. It presents with recurrent cold abscesses, eczema, skeletal defects, and high levels of IgE. The defect is 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

Severe combined immunodeficiency disease (SCID): This is a group of disorders that 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. SCID may be inherited as an AR or X-linked disorder. Common causes include defects in the gamma chain of the IL-2 receptor (X-linked), mutations in the tyrosine kinase ZAP70 gene, mutations in Janus Kinase 3, RAG1 or RAG2 recombinase enzyme mutations (Omenn syndrome, presenting with erythroderma, skin peeling, eosinophilia, and increased IgE), and adenosine deaminase (ADA) or PNP deficiency. In SCID caused by deficiency of ADA or Purine Nucleoside Phosphorylase (PNP), there is an accumulation of dATP (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 synthesis of the mRNA for MHC II proteins, or by mutations in the TAP protein for MHC I.

Low levels of TREC (T cell receptor excision circles) are used to diagnose SCID in newborn screening. Hematopoietic stem cell transplantation, ideally from a sibling, is the standard treatment for infants with SCID. Children with SCID due to 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.

Immunodeficiency disorders

Immunodeficiency diseases may involve deficiencies of T cells, B cells, both (combined), phagocytes, or complement.

T cell disorders mainly cause recurrent viral, fungal, and intracellular bacterial infections, and they increase the risk of malignancy.
B cell disorders mainly cause recurrent bacterial infections, especially with encapsulated bacteria such as Pneumococci and H. influenzae.
Complement or phagocytic deficiencies also commonly present with recurrent pyogenic infections.

Deficiency primarily of humoral immunity

Selective IgA immunodeficiency: This is the most common primary immunodeficiency. Individuals have a complete absence or severe deficiency of IgA, which is important for immune defense in the respiratory and gastrointestinal tracts. Other immunoglobulins are present in normal amounts, although some patients may have low levels of IgG2 and IgG4. Patients are prone to allergies, respiratory, gastrointestinal, and mucosal infections, diarrhea, and autoimmune diseases. Many patients appear normal and have relatively mild disease. Patients with IgA deficiency should not be treated with immunoglobulins or given blood transfusions because of the risk of allergic reactions and depletion of already low levels of IgA.
Common variable immunodeficiency: This is caused by defects in B cell function, leading to deficiency of two or more immunoglobulins (such as IgG and IgA or IgM). Patients show a poor response to vaccination with measles and influenza vaccines. Some individuals have 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 (for example, pneumonia), along with diarrhea and weight loss. Lymphadenopathy and splenomegaly may be present. Autoimmune disorders are more common, including rheumatoid arthritis, autoimmune thrombocytopenia, and hemolytic anemia. There is an increased risk of non-Hodgkin lymphoma and gastric cancer.
Hyper IgM syndrome: This is an AR or X-linked recessive disorder caused by mutations in the gene encoding CD40 ligand (CD40LG) in CD4 helper T cells. As a result, the interaction between CD40 on B cells and CD40 ligand on T cells does not occur, which blocks class switching from IgM to other immunoglobulin types. Patients have a high concentration of IgM but low IgG, IgA, and IgE. T and B cell numbers are normal, and neutropenia may occur in some cases. Individuals present with frequent infections such as pneumonia, sinusitis, otitis, chronic diarrhea, and failure to thrive. They may develop autoimmune disorders, CNS infections, and lymphomas.
X-linked or Bruton’s agammaglobulinemia (XLA): This is an X-linked immunodeficiency caused by mutations in the BTK (Bruton’s tyrosine kinase) gene, leading to a block in B cell development and a lack of antibodies. Infants with XLA are protected during the first two months of life due to maternally transferred antibodies. After this period, they develop recurrent bacterial infections such as pneumonia, bronchitis, otitis, conjunctivitis, sinusitis, and chronic diarrhea. B cells are very low or absent, and immunoglobulin levels are also low.

Deficiency primarily of cell-mediated immunity

Wiskott Aldrich Syndrome: This is an X-linked recessive disorder caused by a mutation in the WAS gene, which encodes WASP. WASP relays signals from the surface of blood cells to the actin cytoskeleton, affecting cellular mobility and adhesion. IgG and IgA levels are normal, and cell-mediated immunity (CMI) is variable. Microplatelets are seen. Patients have recurrent pyogenic, viral, and fungal infections, eczema, and bleeding due to thrombocytopenia. There is an increased risk of autoimmune disorders such as rheumatoid arthritis, vasculitis, and hemolytic anemia.
DiGeorge syndrome or thymic aplasia or velocardiofacial syndrome: In thymic aplasia, both the thymus and parathyroids fail to develop normally due to a defect in the third and fourth pharyngeal pouches. It is caused by a deletion on chromosome 22q and is inherited as AD. Risk factors include maternal DM and 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, a small jaw, and a 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.
Chronic mucocutaneous candidiasis: This refers to a group of heterogeneous disorders characterized by persistent, debilitating, and/or recurrent infections of the skin, nails, and mucous membranes, mainly with the fungal pathogen Candida albicans. It may be associated with DiGeorge syndrome and is seen with inherited or acquired T cell deficiencies.
Job’s Syndrome (Hyper IgE syndrome): This is inherited as AD, with a more severe AR form. It presents with recurrent cold abscesses, eczema, skeletal defects, and high levels of IgE. The defect is 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

Severe combined immunodeficiency disease (SCID): This is a group of disorders that 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. SCID may be inherited as an AR or X-linked disorder. Common causes include defects in the gamma chain of the IL-2 receptor (X-linked), mutations in the tyrosine kinase ZAP70 gene, mutations in Janus Kinase 3, RAG1 or RAG2 recombinase enzyme mutations (Omenn syndrome, presenting with erythroderma, skin peeling, eosinophilia, and increased IgE), and adenosine deaminase (ADA) or PNP deficiency. In SCID caused by deficiency of ADA or Purine Nucleoside Phosphorylase (PNP), there is an accumulation of dATP (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.