Predominantly antibody deficiency

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Immunodeficiency Affecting Cellular and Humoral Immunity
Combined Immunodeficiency
Predominantly Antibody Deficiency
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Congenital Defects of Phagocytes
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Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Anmol Pitliya, M.B.B.S. M.D.[3]

Classification

Predominantly antibody deficiencies

Hypogammaglobulinemia

Other antibody deficiencies

Hypogammaglobulinemia

Predominantly antibody deficiencies (A): Hypogammaglobulinemia

Serum immunoglobulin assays : IgG, IgA, IgM, IgE

IgG, IgA, and/or IgM ↓↓ → B Lymphocyte (CD19+) enumeration (CMF)

B absent

B >1%

X-Linked Agammaglobulinemia

Common Variable Immunodeficiency Phenotype

CD19 deficiency

µ heavy chain Def

CVID with no gene defect specified

CD20 deficiency

Igα def

PIK3CD mutation(GOF),PIK3R1 deficiency(LOF)

CD21 deficiency

Igβ def

PTEN deficiency(LOF)

TRNT1 deficiency

BLNK def

CD81 deficiency

NFKB1 deficiency

λ5 def

TACI deficiency

NFKB2 deficiency

PI3KR1 def

BAFF receptor deficiency

IKAROS deficiency

E47 transcription factor def

TWEAK deficiency

ATP6AP1 deficiency

Mannosyl-oligosaccharide glucosidase deficiency (MOGS)

TTC37 deficiency

IRF2BP2 deficiency

Other Antibody deficiencies

Predominantly antibody deficiencies (B): Other antibody deficiencies

Serum Immunolobulin Assays: IgG, IgA, IgM, IgE

Severe Reduction in Serum IgG and IgA with NI/elevated IgM and Normal Numbers of B cells: Hyper IgM Syndromes

Isotype, Light Chain, or Functional Deficiencies with Generally NI Numbers of B cells

High B cell numbers due to constitutive NF-kB activation

AID deficiency

Selective IgA deficiency

CARD11 Gain of Function

UNG deficiency

Transient hypogammaglobuliemia of infancy

INO80

IgG subclass deficiency with IgA deficiency

MSH6

Isolated IgG subclass deficiency

Specific antibody deficiency with normal Ig levels and normal B cells

Ig heavy chain muations and deletions

Kappa chain deficiency

Selective IgM deficiency

X-linked Agammaglobulinemia

It is an X linked disease first described by Bruton in 1952.It is caused by the mutation of BTK gene (present on the long arm of X chromosome) which encodes for the protein Bruton tyrosine kinase,which is mainly associated with the maturation and differentiation of the pre B cell. The disruption of this protein can therefore lead to significant decrease in all antibody isotypes, due to failure of Ig heavy chain rearrangement.

• Affected individuals generally present between 3 months to 3 years of age, with almost 90% becoming symptomatic by 5 years of age.
• Presence of maternal immunoglobulins provide transient protection, concealing symptoms of the disease and preventing early detection.
• Physical examination typically shows absence of lymph nodes.
• Patients are susceptible to recurrent infections with encapsulated organisms and enteroviruses, primarily effecting respiratory and gastrointestinal tracts.
• Laboratory findings show defect in humoral immunity with absence or negligible amount of IgM, IgG, and IgA, as well as <2% of B cells lymphocytes. Neutropenia can also be seen.
• Treatment is mainly via haematopoietic stem cell therapy and through replacement of immunoglobulins either by intravenous or subcutaneous routes. Recurrent infections are prevented and treated by antibiotics.

For more information on X-linked agammaglobulinemia, click here.

µ Heavy Chain Deficiency

• Autosomal recessive (AR) transmission.
• It is caused by mutation of µ heavy chain(IGHM) on chromosome 14.
• This mutation is phenotypically similar to X-linked agammaglobulinemia, but unlike X-linked agammaglobulinemia can also be seen in females, yet there has been a study that provides data showing clinically significant difference between the two.
• Treatment is mainly via replacement of immunoglobulins by intravenous or subcutaneous routes, haematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

Igα Deficiency

• Autosomal recessive (AR) transmission.
• Mutation of Igα(CD79α) a component of B cell receptor(BCR). Mutations in Pre-BCR complex many times lead to truncation of B cell development.
• It causes a B cell defect which leads to a clinical picture similar to X-linked agammaglobulinemia.
• Patients have increased susceptibility to bacterial infections and otitis media.
• Diagnosis is mainly by polymerase chain reaction (PCR) or single starnd conformational polymosrphism analysis(SSCA).
• Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, haematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

Igβ Deficiency

• Autosomal recessive (AR) transmission.
• Caused by mutation in the CD79B gene on chromosome 17.
• Patients generally present with reduced immunologlobins which leads t frequent bactirial infections of upper and lower respiratory tract similar to other agammaglobulinemia like X-linked agammaglobulinemia.

BLNK Deficiency

• Autosomal recessive (AR) transmission.
• BLNK gene on chromosome 10 encodes for B cell linker protein (BLNK, SLC-65) and is crucial for the development of pre B cell.
• Patients generally present with recurrent bacterial infections, otitis media and upper and lower respiratory tract infections simillar to X-linked agammaglobulinemia.
• Treatment is mainly via replacement of immunoglobulins by intravenous or subcutaneous routes, haematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

λ5 Deficiency

• Autosomal recessive (AR) transmission.
• λ5(IGLL1) coponent of B cell receptor mutation.
• Leads to clinical features similar to X-linked agammaglobulinemia.