Etiology

Primary hypogammaglobulinemia

Primary hypogammaglobulinemia can be explained in some cases by known genetic defects (e.g., the Bruton tyrosine kinase [BTK] gene mutation in X-linked agammaglobulinemia [XLA]).[1] In other cases, there may be single-gene defects that are as yet unrecognized, and in further cases there may be a polygenic basis.

Many gene defects have been identified in severe combined immunodeficiency (e.g., defects of recombinase activating gene 1 or 2, or defects in the interleukin 7 receptor alpha chain). An increasing number of single-gene defects have been described in patients with a common variable immunodeficiency (CVID) phenotype; however, there are many CVID patients without an identified single-gene defect. Additionally, alterations in transmembrane activator and CAML-interactor (TACI), B-cell activating factor receptor (BAFF receptor), and MutS protein homolog 5 (MSH5) may act as contributing polymorphisms in a few cases originally diagnosed as CVID.[13][14][15]

Secondary hypogammaglobulinemia

Secondary hypogammaglobulinemia has various causes related to impaired production or increased loss of immunoglobulins.[3][16] Impaired production can be associated with hematologic malignancy (e.g., myeloma, leukemia, lymphoma, B-cell chronic lymphocytic leukemia), medication (e.g., rituximab, carbamazepine, phenytoin, corticosteroids, disease-modifying antirheumatic drugs, antimalarials, cytotoxic or immunosuppressive therapy), radiation, or malnutrition.[2] Increased loss of immunoglobulins can be associated with protein-losing enteropathy (e.g., from inflammatory bowel disease, autoimmune enteropathy, intestinal lymphangiectasia) or severe nephrotic syndrome (although most patients with nephrotic syndrome have preserved immunoglobulin levels).[2] 

The European Society for Immunodeficiencies has published a differential diagnosis list for hypogammaglobulinemia. European Society for Immunodeficiencies: diagnostic criteria for PID Opens in new window

Pathophysiology

Immunoglobulins are produced by plasma cells that differentiate from B lymphocytes. There are 5 isotypes (IgM, IgA, IgG, IgE, and IgD) and 4 IgG subclasses (IgG1, IgG2, IgG3, and IgG4). High-affinity antibody responses in the blood are typically IgG isotype and depend on T-cell help.

The primary antibody deficiency syndromes and many of the secondary causes of hypogammaglobulinemia can result in a defect in humoral immunity. This can lead to serious and/or recurrent infections, particularly of the upper and lower respiratory tract but also of the gastrointestinal tract, skin, and brain. Chronic and recurrent infections with suboptimal treatment can lead to permanent damage, such as bronchiectasis. Encapsulated bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae) are the most common pathogens in hypogammaglobulinemia, but mycoplasma and viruses may also be involved.

The predominantly antibody deficiency syndromes that cause marked reduction of IgG levels include CVID, XLA, autosomal-recessive agammaglobulinemias, and immunoglobulin class-switch recombination defects (e.g., X-linked immunodeficiency with hyper-IgM).

Immune dysregulation and consequent development of autoimmunity in CVID leads to autoimmune disorders in 25% to 30% of patients (most commonly immune thrombocytopenic purpura and autoimmune hemolytic anemia).[13] A sarcoid-like illness with noncaseating granulomata may occur and can affect the lungs, liver, spleen, skin, gastrointestinal tract, and lymph nodes, among other locations. Nodular lymphoid hyperplasia, malabsorption, inflammatory bowel disease, and celiac-like enteropathies occur in 20% of patients.[17] Immune surveillance may be reduced in CVID as a consequence of immune dysregulation. This is associated with increased risk of non-Hodgkin lymphoma, gastric cancer, and other types of malignancy depending on the underlying immune defect.[18][19] However, not all hypogammaglobulinemic states are associated with an increased risk of malignancy.

In combined immunodeficiencies, there are both cellular and antibody defects. The underlying defect may affect some or all of the lymphocyte lineages (B lymphocytes, T lymphocytes, and natural killer lymphocytes). Some defects occur in the T cells only, and because B cells require T-cell help, this may result in hypogammaglobulinemia. The immunodeficiency tends to be severe (e.g., severe combined immunodeficiency), and infections usually start soon after birth.

Primary immunodeficiency diseases with a normal total IgG but a reduction in specific components (e.g., IgA deficiency, IgG subclass deficiency, impaired specific antibody production) are often less severe than those associated with a reduction in total IgG. Other antibodies present may compensate.

Classification

Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies (IUIS) Expert Committee[1]

A total of 485 inborn errors of immunity have been described, with phenotypes including infection, malignancy, allergy, autoimmunity, and autoinflammation. Primary immunodeficiency (PID) disorders can have diverse presentations and can affect different parts of the immune system, including immunoglobulin production.

There are 10 subsections of the IUIS PID classification:

  • Immunodeficiencies affecting cellular and humoral immunity

  • Combined immunodeficiencies with associated or syndromic features

  • Predominantly antibody deficiencies

  • Diseases of immune dysregulation

  • Congenital defects of phagocyte number or function

  • Defects in intrinsic and innate immunity

  • Autoinflammatory disorders

  • Complement deficiencies

  • Bone marrow failure

  • Phenocopies of inborn errors of immunity.

Predominantly antibody deficiencies that cause hypogammaglobulinemia are grouped under the following four headings.

  • Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia

    • BTK deficiency, XLA

    • Mu heavy-chain deficiency

    • Lambda-5 deficiency

    • Ig-alpha deficiency

    • Ig-beta deficiency

    • B-cell linker protein deficiency

    • p110-delta deficiency

    • p85 deficiency

    • E47 transcription factor deficiency

    • SLC39A7 deficiency

    • Hoffman syndrome/TOP2B deficiency

    • FNIP1 deficiency

    • PU1 deficiency.

  • Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low numbers of B cells, CVID phenotype

    • Common variable immunodeficiency disorders with no gene defect specified (CVID)

    • Activated p110-delta syndrome

    • PTEN deficiency (loss of function)

    • CD19 deficiency

    • CD81 deficiency

    • CD20 deficiency

    • CD21 deficiency

    • TACI deficiency

    • BAFF receptor deficiency

    • TWEAK deficiency

    • TRNT1 deficiency

    • NFKB1 deficiency

    • NFKB2 deficiency

    • IKAROS deficiency

    • IRF2BP2 deficiency

    • ATP6AP1 deficiency

    • ARHGEF1 deficiency

    • SH3KBP1 deficiency

    • SEC61A1 deficiency

    • RAC2 deficiency

    • Mannosyl-oligosaccharide glucosidase deficiency

    • PIK3CG deficiency

    • BOB1 deficiency.

  • Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper IgM

    • Activation-induced cytidine deaminase (AID) deficiency

    • Uracil-DNA glycosylase (UNG) deficiency

    • INO80 deficiency

    • MSH6 deficiency

    • CTNNBL1 deficiency

    • APRIL deficiency.

  • Isotype, light-chain, or functional deficiencies with generally normal numbers of B cells

    • Immunoglobulin heavy chain mutations and deletions

    • Kappa chain deficiency

    • Isolated IgG subclass deficiency

    • IgG subclass deficiency with IgA deficiency

    • Selective IgA deficiency

    • Specific antibody deficiency with normal immunoglobulin concentrations and normal B cells

    • Transient hypogammaglobulinemia of infancy

    • CARD 11 (gain of function)

    • Selective IgM deficiency.

Secondary hypogammaglobulinemia

Secondary hypogammaglobulinemia may be caused by decreased production or increased loss of immunoglobulins.

Immunoglobulin production may be impaired due to the following:[2]

  • Hematologic malignancy and premalignant conditions (e.g., myeloma, leukemia, lymphoma, B-cell chronic lymphocytic leukemia)

  • Medication (e.g., rituximab, corticosteroids, disease-modifying antirheumatic drugs, anticonvulsants such as carbamazepine and phenytoin, antimalarials, cytotoxic or immunosuppressive drugs) or radiation

  • Malnutrition.

Increased immunoglobulin loss may be due to the following:[2]

  • Protein-losing enteropathy (e.g., from inflammatory bowel disease, autoimmune enteropathy, intestinal lymphangiectasia)

  • Severe nephrotic syndrome (although most patients with nephrotic syndrome have preserved immunoglobulin levels)

  • Burns or other traumas leading to loss of fluids.

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