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common variable immune deficiency

MIM.240500

Monday 7 March 2005

Definition: Common variable immunodeficiency (CVID) is a heterogeneous disease that results in hypogammaglobulinemia, diminished ability to produce antibody in response to vaccines or infections, and a propensity for infection.

The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B cells is usually in the normal range, but can be low. Most individuals with CVID have onset of infections after age 10 years.

CVID represents the most common form of primary immunodeficiency disorders and is the most common form of primary antibody deficiency. Approximately 10 to 20% of patients with a diagnosis of CVID have a family history of the disorder.

Common variable immunodeficiency encompasses a collection of disorders unified by dysfunctional B-cell differentiation such that B cells fail to secrete immunoglobulin. The incidence is estimated at 1:50,000 to 200,000 in the general population.

The diagnosis is made upon finding a decrease below 2 standard deviations in at least 2 of the 3 major immunoglobulin classes (IgA, IgG, and IgM), impaired antibody production in response to infection and/or vaccines, normal or near-normal T-cell immunity, and exclusion of other causes of immunodeficiency.

Most CVID cases are sporadic (19% to 22% of cases are familial).

It usually presents in the second or third decade. Delay in diagnosis can lead to serious sequelae including infection and death.

CVID results from a dysfunction of B-cell differentiation, though T-cell dysregulation may also be seen.

CVID is the second most common primary immunodeficiency syndrome, after selective IgA deficiency. CVID is diagnosed by a reduction in serum immunoglobulin (IgG, IgA, and/or IgM) levels, and absence or impaired antibody responses to vaccination; and exclusion of other causes of immunodeficiency.

Common variable immunodeficiency (CVID) is associated with low serum-immunoglobulin concentrations, defective specific-antibody production and an increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts.

The term "common variable immunodeficiency" is used to designate a group of as yet undifferentiated syndromes. All are characterized by defective antibody formation. The diagnosis is based on the exclusion of other known causes of humoral immune defects.

CVID are predisposed to infections, particularly respiratory tract infections with encapsulated and atypical bacteria. Bronchiectasis is a frequent complication.

Types

- CVID1 (MIM.607594), caused by homozygous mutation in the ICOS gene (MIM.604558) on chromosome 2q33.
- CVID2 (MIM.240500), caused by mutation in the TACI gene (TNFRSF13B; MIM.604907)
- CVID3 (MIM.613943), caused by mutation in the CD19 gene (MIM.107265);
- CVID4 (MIM.613494), caused by mutation in the BAFFR gene (TNFRSF13C; MIM.606269);
- CVID5 (MIM.613495), caused by mutation in the CD20 gene (MIM.112210);
- CVID6 (MIM.613496), caused by mutation in the CD81 gene (MIM.186845)

Synopsis

- short stature

- recurrent bacterial infections (encapsulated bacteria, mycoplasma)

  • acute sinusitis
  • acute otitis media
  • conjunctivitis
  • recurring infectious pneumonia with frequent bronchiectasis
  • meningitis

- digestive anomalies

  • Helicobacter gastritis (#10369708#)
  • Helicobacter-associated gastric adenocarcinoma (#10369708#)
  • Helicobacter-associated gastric dysplasia (#10369708#)
  • chronic active gastritis (#10369708#)
  • multifocal atrophic gastritis (#10369708#)
  • intestinal nodular lymphoid hyperplasia (NLH)
  • malabsorption
  • giardiasis
  • sprue
  • digestive infections
    • CMV enteritis (#14746434#)

- chronic persisting hepatitis (#6604451#)
- chronic granulomatous inflammation (#16091208#)

  • systemic granulomatosis

- lymphoproliferative lesions (#1334378#)

  • reactive lymphoid hyperplasia
  • atypical lymphoid hyperplasia
  • B-cell lymphomas
    • BALT lymphoma (pulmonary marginal zone B-cell lymphoma) (#11223743#)
    • MALT lymphoma (mucosal marginal zone B-cell lymphoma) (#16321869#)

- autoimmune diseases

  • atrophic gastritis
  • arthritis
  • hemolytic anemia

- granulomatous-lymphocytic interstitial lung disease (GLILD) (31% of associated lymphoproliferative disease)(#15316526#)

  • granulomatous lung disease (GLD)
  • pulmonary lymphoid hyperplasia
    • lymphocytic interstitial pneumonia (LIP)
    • follicular bronchiolitis (BALT hyperplasia)

- organizing penumonia (#10940808#)

  • BOOP (bronchiolitis obliterans organizing pneumonia)

- usual interstitial pneumonitis (UIP)

- granulomatous lesions (#15320909#)

  • non-caseating granulomas
  • chronic granulomatous inflammation (#10881789#, #9341059#)

- digestive anomalies (#8827031#)

  • malabsorption with mild to severe villous atrophy
  • Giardia infection (intestinal giardiasis)
  • small bowel lymphoma associated with nodular lymphoid hyperplasia
  • intestinal foamy histiocytes in the lamina propria, resembling Whipple disease or chronic granulomatous disease, with numerous apoptotic bodies in crypts
  • colitis with features similar to ulcerative colitis
  • poorly formed granulomas
  • nodular lymphoid hyperplasia

- autoimmune disorders

  • autoimmune cytopenias

- pityriasis lichenoides
- splenomegaly
- choroidal granulomas (#16402965#)

Synopsis

- several patterns of inheritance (autosomal recessive, autosomal dominant, and X-linked)
- possible sporadic cases
- Among populations of European origin, common variable immunodeficiency is the most frequent of the primary specific immunodeficiency diseases.
- It affects men and women equally.
- The usual age at presentation is the second or third decade of life.

- recurrent pyogenic sinopulmonary infections

- opportunistic infections

  • encapsulated bacteria
  • mycoplasma
  • Toxoplasma gondii (#15320909#)
  • disseminated histoplasmosis (#14533988#)
  • CMV (cytomegalovirus)
  • Pneumocystis carinii
  • mycobacteria
  • various fungi

- viral infections

  • recurrent attacks of herpes simplex virus (HSV)
  • herpes zoster (20%)

- unusual enteroviral infections

  • chronic enteroviral meningoencephalitis
  • syndrome resembling dermatomyositis

- pulmonary anomalies

  • serious chronic obstructive lung disease
  • bronchiectases (#17400689#)
  • GLILD

- digestive anomalies (#18043034#)

  • nodular lymphoid hyperplasia of the GI tract
  • CVID-associated autoimmune atrophic gastritis
  • CVID-associated gastritis
  • CVID-associated gastric mucosal dysplasia
  • CVID-associated gastric adenocarcinoma
  • CVID-associated autoimmune enteropathy
  • CVID-associated lymphocytic colitis
  • CVID-associated active colitis
  • CVID-associated granulomatous colitis
  • CVID-associated digestive infections
    • CVID-associated chronic Giardia lamblia infection

- Lymphomas

- gastrointestinal tumors

  • gastric adenocarcinoma (Risk x50-fold)

- diffuse lymphadenopathy
- splenomegaly
- striking reactive follicular hyperplasia
- gastrointestinal tract

  • nodular lymphoid hyperplasia
  • malabsorption with weight loss, diarrhea, hypoalbuminemia. vitamin deficiencies.
  • inflammatory bowel diseases (IBDs)

- autoimmune disorders

  • pernicious anemia
  • hemolytic anemia
  • thrombocytopenia
  • neutropenia

- noncaseating tuberculoid granulomas occur in the skin, the gut, and other viscera

Immunology

- defective antibody formation

  • decreased serum IgG concentrations
  • decreased serum IgA
  • decreased serum IgM

- no convincing evidence of any intrinsic B-cell defects.

  • The number of B cells may be reduced but with they can produce and secrete immunoglobulins appropriate stimulation.
  • B cells are immature. The findings in common variable immunodeficiency are consistent with insufficient in vivo stimulus for B-cell activation rather than an intrinsic failure of B cells to differentiate.

- Relatives of patients with common variable immunodeficiency

  • unusually high incidence of IgA deficiency
  • increased incidence of autoimmune disorders
  • increased incidence of autoantibodies (including antilymphocyte antibodies)
  • increased incidence of malignant conditions

Associations

- primary ciliary dyskinesia (#17438081#)
- malabsorption syndrome (#17400689#)

Malignancies

CVID has been shown to predispose to a number of malignancies, including lymphoma and adenocarcinoma of the GI tract (up to 30%)

Autoimmune disorders (up to 20%)

Autoimmune disease affected the GI tract/hepatobiliary system (autoimmune metaplastic atrophic gastritis, autoimmune enteritis, and autoimmune hepatitis), as well as systemically.

Physiopathology

- Families whose members include persons with common variable immunodeficiency and IgA deficiency often have certain fixed haplotypes in the MHC.

- One or more genes in the MHC may be involved in the pathogenesis of common variable immunodeficiency and IgA deficiency.

- Since immature B cells in common variable immunodeficiency appear to be functionally intact, the defect might logically reside in the T-cell component of the interaction between B cells and T cells requisite for B-cell maturation. However, it is often difficult to interpret studies of T cells in common variable immunodeficiency, because of the activation of T cells that is probably a result of recurrent or chronic infections or infusions of intravenous immune globulin.

- In most patients with common variable immunodeficiency, stimulation of T-cell receptors produces diminished responses and there is decreased gene transcription of cytokines such as interleukin-2, interleukin-4, interleukin-5, and interferon-.68,69 Decreased production of interleukin-2 after direct stimulation of T-cell receptors70 is correlated with diminished expression of CD40 ligand and may reflect an abnormality in CD4+ T cells in common variable immunodeficiency. This abnormality of T-cell triggering can be bypassed by direct activation of signal transduction.

- Thus, many patients with common variable immunodeficiency appear to have defective interactions between T cells and B cells. Defective T-cell signal transduction could contribute to the diminished humoral immunity found in these disorders in the presence of immature but otherwise potentially normal B cells.

- In the absence of appropriate T-cell signaling, B cells would fail not only to produce antibody, but also to proliferate and differentiate, which would result in both the decreased numbers and the arrested maturation of B cells seen frequently in common variable immunodeficiency.

Biology

- low plasma cells number in bone marrow
- normal numbers of T cells
- variable degree of T cell dysfunction
- normal numbers of surface immunoglobulin positive B cells
- markedly reduced IgA levels
- markedly reduced IgG levels
- reduced IgM levels
- anti-IgA antibodies commonly present

Transmission

- genetic CVID

  • autosomal recessive inheritance
  • autosomal dominant inheritance
  • ICOS deficiency (MIM.607594) by mutations in ICOS gene(MIM.604558)
  • sporadic cases

- drug-induced CVID

  • sulfasalazine
  • hydantoin
  • carbamazepine
  • levamisole

Etiology

- germline mutations of TNFRSF13B (TACI) in common variable immunodeficiency (CVID) (MIM.240500) (#16007087#)

  • In a subset of CVID patients, various mutations have been discovered in TACI [Transmembrane Activator and Calcium-modulator and cyclophilin ligand (CAML) Interactor] encoded by TNFRSF13B located on the short arm of chromosome 17. (#18043034#)
  • TNFRSF13B (TACI) is expressed on peripheral B cells, and is a member of the TNF-like receptor family that transduces signals involved in cell survival, apoptosis, and isotype switching. (#18043034#)
  • The ligands for TACI include BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand), both in the TNF ligand family, expressed by monocytes and dendritic cells as either soluble or bound ligand. BAFF and APRIL can induce isotype switching, and in the absence of their receptor (TACI), no plasma cell maturation or immunoglobulin production can occur. (#18043034#)
  • Five percent to 10% of cases of CVID may carry at least one of many identified mutations in TNFRSF13B, and a mutation has also been found in a patient with IgA deficiency. (#18043034#)
  • Further support that TACI may play a role in the pathogenesis of CVID is that TNFRSF13B -/- mice show an increased risk of lymphoproliferative and autoimmune disorders, a phenotype reminiscent of CVID. (#18043034#)

IgA deficiency

A strong relationship exists between CVID and IgA deficiency. In CVID patients, IgA seems to be affected to a greater degree than IgG, followed by IgM. (#18043034#)

A linkage between CVID and IgA deficiency in the susceptibility locus within the major histocompatibility complex has been described, especially between class III markers D821/D823 and HLA-B8 on chromosome 6, a region that encompasses 21 genes including tumor necrosis factor alpha (TNF-α) and lymphotoxins α and β. (#18043034#)

It is likely that some of the variability of CVID comes from mutations that interrupt B-cell function at specific steps along these complex pathways. Non-HLA regions have also been linked to CVID. (#18043034#)

Prognosis

The use of high-dose intravenous gamma globulin has significantly decreased the frequency and severity of infections in patients with CVID.

Consequently, the noninfectious diffuse lung disease complications of CVID, such as the granulomatous lesions and lymphoproliferative disorders (eg, lymphomas, lymphocytic interstitial pneumonia [LIP], and follicular bronchiolitis, GLILD), are an increasing cause of morbidity and mortality.

The mortality rate ranges between 23% and 27%.

Treatment

The mainstay of treatment is replacement therapy with pooled human immunoglobulin delivered intravenously (IVIG) or subcutaneously.

IVIG treatment is generally safe although allergic reactions have been reported. More problematic aspects of treatment involve management of associated end-organ damage (eg, chronic lung or sinus disease resulting from previous infections) and autoimmune or chronic inflammatory diseases (eg, IBD, autoimmune cytopenias, and endocrinopathy).

References

- Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007 Dec;31(12):1800-12. PMID: #18043034#

- Castigli E, Geha RS. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6; PMID: 16630927

- Knight AK, Cunningham-Rundles C. Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmun Rev. 2006 Feb;5(2):156-9. PMID: #16431351#

- Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8. PMID: #16007087#

- Bayry J, Hermine O, Webster DA, Levy Y, Kaveri SV. Common variable immunodeficiency: the immune system in chaos. Trends Mol Med. 2005 Aug;11(8):370-6. PMID: #15996517#

- Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004 Aug;114(2):415-21. PMID: #15316526#

- Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996 Oct;20(10):1240-52. PMID: #8827031#

- Sander CA, Medeiros LJ, Weiss LM, Yano T, Sneller MC, Jaffe ES. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. 1992 Dec;16(12):1170-82. PMID: #1334378#