30 October 2009

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.

5 comments:

  1. This is really interesting. T cells have 2 surface molecules which bind B7 on antigen-presenting cells. CD28 is co-stimulatory, and CTLA4 is inhibitory, to T cell activation. In a T cell response, CD28 acts first so the cell is activated, then it is downregulated while CTLA4 comes up; so the response can be terminated. There are several autoimmune diseases with linkage to CTLA4 polymorphisms.

    ReplyDelete
  2. That's an interesting correlation - it's understandable that dysfunction in the action of CTLA4 and ICOS would lead to IgAD and CVID, and HLA variants to celiacs, but is there any indication of a known mechanism by which CTLA4 or ICOS would directly cause/influence celiacs? Was there any correlation tested between DQ2,DQ8 and the CTLA4-ICOS variation?

    ReplyDelete
  3. Thanks, Dr. Cohen. I will update the entry to more accurately reflect CTLA4's inhibitory nature. As a follow-up to your comment on other autoimmune diseases associated with CTLA4, the article mentions that the 2q33 locus that harbors CD28, CTLA4, and ICOS has been studied for type I diabetes and autoimmune thyroid disease. In addition, a quick Pubmed search revealed these other associations with CTLA4: lupus, rheumatoid arthritis, primary biliary cirrhosis and possibly vitiligo and Addison's disease.

    ReplyDelete
  4. Mike, Thanks for your comments. As far as possible mechanisms, the only thing I really found in the article was the authors' postulation that lower levels of expression of ICOS and/or comparatively higher levels of CTLA4 or soluble CTLA4 affect the risk of CD, CVID, and IgAD. They did not even mention DQ2, DQ8 in the article to my knowledge.

    ReplyDelete
  5. In regards to the expression levels of ICOS and CTLA4 and its correlation with the onset of IgAD and CVID, I am interested in their analysis of the SNPs located near the genes encoding ICOS and CTLA4. Where exactly are these SNPs located (intergenic regions, promoter region, 3'-UTR...). I'm not too familiar with SNPs but could the nucleotide variations and given its location be acting as an enhancer/suppressor of gene expression and consequently pressuring the outcome of ICOS and CTLA4 expression levels? I think it would be interesting to examine the variability within the nucleotide changes (genotypes) across patients and compare them with expression levels of ICOS and CTLA4.

    ReplyDelete