Genetics The cause of<unk> , while not fully understood, is by definition related to celiac disease. Individuals are genetically predisposed to develop celiac disease because of the specific types of HLA-DQ proteins expressed by their antigen-presenting<unk> s (APC). HLA-DQ proteins are on the surface of APC and function to present foreign or self antigens to the T<unk>  receptors (TCR) expressed on the surface of T-cells and thereby to stimulate these<unk> s either to initiate or suppress immune responses to the presented antigens. HLA-DQ proteins are composed of α and β polypeptide chains encoded by the HLA-DQA1 and HLA-DQB1 genes, respectively. Since there are several different alleles (i.e. gene variants) at these two genetic loci, individuals are usually heterozygous, i.e. have inherited different alleles from each parent at each locus; uncommonly, however, individuals are homozygous at one or both loci because their parents have the same alleles at one or both loci. The HLA-DQ proteins that predispose individuals to coeliac disease bind and respond specifically to gluten-related antigens presented to them by APC. The genetic predisposition to develop coeliac disease is clinically determined by identifying the serotypes of an individual's APC's HLA-DQ proteins using serotype-specific antibody preparations and/or by identifying the alleles at an individual's HLA-DQA1 and HLA-DQB1 genetic loci. Studies show that: * Celiac disease affects ~1% of the population in most parts of the world. * Ninety to one hundred percent of patients with coeliac disease have inherited genes at the HLA-DQ locus that encode HLA-DQ2 and/or HLA-DQ8 serotype proteins. * About 2-3% of individuals who inherit these HLA-DQ2 and/or HLA-DQ8 serotypes develop coeliac disease. * About 90% of coeliac disease patients are homozygous for (i.e. inherited from both parents) either the HLADQA1*0501 or HLADQA1*0505 alleles at the HLA-DQA1 locus plus either the HLADQB1*0201 or HLA-DQB1*0202 alleles at the HLA-DQB1 locus; <5% of coeliac disease patients are heterozygous (i.e. inherited from just one parent) for these alleles; and 5-10% of coeliac disease patients have inherited HLA-DQA1*03 plus HLA-DQB1*0302 alleles at the respective HLA-DQA1 and DAQB1 loci. * Less than 1% of all individuals with coeliac disease develop<unk> . * Individuals homozygous for the HLADQB1*0201 allele at the HLA-DQB1 locus develop a particularly severe and tissue-damaging form of coeliac disease and have a greatly increased rate of developing<unk> . * The vast majority of patients with coeliac disease who develop<unk>  have either the HLADQA1*0501 or HLADQB1*0201 allele (see previous paragraphs) at the HLA-DQB1 locus. Intraepithelial lymphocytes IEL are a diverse population of lymphocytes, which unlike most peripheral lymphocytes, do not recirculate through the blood and/or lymphatic system but rather reside permanently in the epithelium of various organs. In the GI tract, IEL localize between the epithelial<unk> s lining the colon, small intestine, stomach, and esophagus where they serve to maintain the mucosal barrier, combat infection by pathogens, and regulate immune responses to antigens originating from the diet, pathogens, and damaged tissues. Human IEL are classified into those which express the TCR (i.e. TCL+IEL) and those which do not (i.e. TCR-IEL). TCL+IEL are further divided into 4 subtypes, TCRαβ+CD4+ IEL, TCRαβ+CD4+CD8αα+ IEL, TCRαβ+CD8αβ+ IEL, and TCRλδ+CD8αα+. These subtypes are based on the expression of alpha (α) and beta (β) chain-containing TCR (i.e. αβTCR); gamma (γ) and delta (δ) chain-containing TCR (i.e. γδTCR); CD4; CD8αβ; and/or CD8αα by individual IEL.. A fifth TCL+IEL subtype, TCRαβ+CD8αα+, occurs in mice but its presence in the human intestine is disputed. Human TCR-IEL are also divided into 4 sub-types: their: ILC1-like IEL have morphological and functional similarities to normal intestinal epithelial<unk> s and express NKp46; ICL3-like IEL have morphological similarities to normal epithelial<unk> s and, similar to Th1<unk> s, make Interleukin 17 (IL-17) and Interleukin 22 (IL-22) cytokines and express the RORγt transcription factor and NKp44; iCD3-IEL express iCD3; and iCD8α-IEL express iCD3 and CD8α. CD3 designates a protein complex that is attached to the<unk>  surface membrane whereas iCD3 refers to a CD3 protein complex in which one or more of its proteins resides abnormally in the<unk> 's cytosol Studies suggest that iCD3+IEL are the principal<unk>  type that becomes malignant in<unk>  cases that are not classified as de novo (see next section). These<unk> s also express CD103 and, frequently, CD30. Acquisition of malignancy Coeliac disease patients may be asymptomatic, minimally symptomatic, and/or well-controlled on a gluten-free diet (i.e. a diet free of cereal, rye, wheat, and barley) but nonetheless develop<unk> . About 46% of all AETL cases occur in this setting and have had their malignancy described as de novo<unk> . The remaining ~54% of<unk>  cases develop in coeliac disease patients whose disease becomes refractory to dietary control, exhibits increasing symptoms, and progress over ~4–10 years through Type I refractor coeliac disease (Type 1 RCD) and Type II refractory coeliac disease (Type II RCD) to become<unk> . The rates at which non-refractory celiac disease, Type I RCD, and Type II RCD progress to de novo or<unk>  are <1%, 3-14%, and 33-52%, respectively. De novo<unk>  De novo<unk>  can occur in individuals whose coeliac disease was undiagnosed until<unk>  was found or who have mild/well-controlled coeliac disease. The findings in these patients usually differ little from those found in mild/well-controlled cases that do not progress to<unk> ; their small intestinal mucosa is populated by increased number of IEL and exhibits tissue destruction (e.g. small intestinal villus atrophy), Nonetheless, their IEL are normal-appearing, small<unk> s that on examination are polyclonal (i.e. genetically diverse), express CD3 and CD8, and do not have genetic abnormalities. The mechanism behind the development of<unk>  in these individuals is not understood. Type I refractory coeliac disease Type I RCD patients, who constitute 15-23% of all patients with RCD, are refractory to the gluten diet as evidenced by their worsening symptoms, increased tissue destruction, and rising numbers of TCRαβ+CD*αβ+IEL in tissue lesions. Some Type I RCD patients may have failed to respond to the diet from the onset of their disease. If either cases, these patients show no change in the normal appearance and polyclonal nature of their small intestinal IEL and these IEL show no genetic abnormalities. The cause for these coeliac disease patients progressing to Type I RCD, after excluding the very common problem of failure to fully exclude gluten from their diets, is either due to their genetic makeup (see above section on genetics) or is unknown. Type II refractory coeliac disease Type I RCD patients may progress to Type II RCD as evidenced by their more severe symptoms, increased intestinal tissue destruction, and expanding numbers of intestinal IEL, particularly iCD3+IEL. Their IEL typically consist of genetically different subpopulations of<unk> s that have a monoclonal rearrangement of their TCR and therefore are descendant from a single ancestral<unk> . Subpopulations of these IEL also have one or more of the following genetic abnormalities: trisomy of chromosome 1's long (or "q") arm at position 22-44 (abbreviated 1-q22-24); genomic alterations around the TP53 tumor suppressor gene at position 13.1 on the short or "p" arm of chromosome 17; genomic alterations around the CDKN2A tumor suppressor and CDKN2B<unk>  proliferation regulator at position p21.3 on chromosome 9 that result in loss of heterozygosity for both genes; and/or activating mutations in JAK1 (75% of cases) and STAT3 (25% of cases). In Type II RCD, the same types of abnormal ILE found in the small intestine may be detected in the colon, stomach, mesenteric lymph nodes, blood, bone marrow, and epithelium of the airways and skin. Finally, the small intestinal lesions in Type II RCD contain IL-2 and IL-21 as well as increased levels of IL-15. Laboratory studies indicate that these 3 cytokines acting individually or in synergy are potent stimulators of the JAK1/STAT3 signaling pathway in iCD3+IEL and thereby promote these<unk> s survival (by blocking apoptosis) and proliferation. The small intestinal lesions also contain a tumor necrosis factor which stimulates iCD3+IEL survival and proliferation but does so by activating NF-κB, MAPK, and/or c-Jun N-terminal kinases rather than JAK1/STAT3 signaling pathway. These data suggest that: a) Type II RCD is a low grade lymphoma; 2) the intense inflammation in Type II RCD, perhaps amplified by the cited cytokines, promotes the proliferation, survival, genome instability, and consequential genetic abnormalities in IEL; and 3) one or more of these factors cause the transformation of Type II RD to<unk> . As currently understood, the release of IL-15 by mucosal epithelial<unk> s, the binding of IL-15 to the IL-15Rβ<unk>  surface receptor on iCD3+IEL, and the stimulation thereby of these<unk> s appears particularly important in driving Type II RCD to<unk>  in a significant number of cases. Ulcerative jejunitis Ulcerative jejunitis (also termed chronic ulcerative jejunitis, multifocal ulcerated microlymphomas, ulcerative jejunoilitis, and chronic ulcerative jejunoilitis) is regarded as a rare complications or severe form of Type II RCD in which the jejunum or jejunum plus ileum portions of the small intestine contain multifocal ulcers. Patients with this disorder have a higher risk of developing<unk>  than other Type II RCD patients.<unk>  Besides the genetic gene abnormalities found in Type II RCD, the
Enteropathy-associated T-cell lymphoma
Monomorphic epitheliotropic intestinal T cell lymphoma
Hereditary progressive mucinous histiocytosis
MALT lymphoma
Natural killer cell enteropathy
Duodenal-type follicular lymphoma
Gastric lymphoma
AIDS-related lymphoma