The IgA Deficiency, Celiac Disease, and CVID Link

It is known that patients with celiac disease have a higher incidence of IgA deficiency (IgAD) than the general population. This made me wonder why? Going to the literature, I found an article published earlier this year that has shed some light on the association of the two, as well as, interestingly, common variable immunodeficiency (CVID).

As a review, IgAD is the most common primary immunodeficiency (~1 in 500) and often is asymptomatic. There is a higher risk of autoimmune diseases in these people, however, including 10-fold risk of celiac disease. CVID is a disorder of unknown cause that may manifest at various ages with recurrent bacterial infection. Those with CVID have normal numbers of B cells, but are difficult to induce antibody production. IgAD and CVID have been said to be part of a spectrum of defects in antibody production, and IgAD patients can progress to CVID. Celiac disease is a chronic intestinal inflammatory disorder due to gluten intolerance (gluten is an antigen found in wheat, barley and rye) that can only be treated currently with gluten avoidance (which usually works remarkably well when strictly avoided). Its prevalence is quite high in European populations (1%), and celiac disease is strongly associated with HLA DQ2 and DQ8. CVID has been reported in patients with celiac disease (Béchade D, et al. Common variable immunodeficiency and celiac disease. Gastroenterol Clin Biol. 2004 Oct;28(10 Pt 1):909-12.)

Inducible co-stimulator (ICOS) is a T-cell co-stimulatory receptor that, through its interaction with B-cells, influences immunoglobulin class switching and cytokine secretion. Cytotoxic T-lymphocyte-associated protein-4 (CTLA4) is a negative regulator of T-cell function by interacting with B7-1 and B7-2 on an antigen presenting cell. It may have an important role in tolerance induction. Previously, there has been evidence that CTLA4-ICOS is associated with celiac disease. It would make sense that malfunction of these co-stimulators could also play a role in IgAD and CVID given the nature of these immunodeficiencies. If you can’t class switch from IgG to IgA, for instance, you are IgA deficient.

In this European study, 1600 families or patients with celiac disease, IgAD, or CVID were genotyped for 14-18 genetic markers in the CTLA4-ICOS region. The markers are called SNPs, or single nucleotide polymorphisms. An SNP is “a small genetic change, or variation, that can occur within a person's DNA sequence… [that] serve as biological markers for pinpointing a disease on the human genome map, because they are usually located near a gene found to be associated with a certain disease.”
(http://www.ncbi.nlm.nih.gov/About/primer/snps.html).
They used the prevalence of these SNPs to uncover statistically significant associations between CTLA4-ICOS and IgAD (p = 0.0015), CVID (p = 0.0064), and celiac disease (p = 0.0009). The authors theorize that this association may result because of lower expression of ICOS and/or comparatively higher levels of CTLA4 or soluble CTLA4.

This was the first study to report shared risk gene variants other than HLA among people with IgAD, CVID and celiac disease. Gene “hits” to this region could theoretically lead to development of any or a combination of these disorders, thus, at least in part, answering my question as to why people with celiac disease also get IgA deficiency.

The article is found in Genes and Immunity:
Haimila K, et al. The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. Genes Immun. 2009 Mar;10(2):151-61.