Clinical impact of KIR haplotypes in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic hematopoietic stem cell transplantation.

To evaluate the impact of killer immunoglobulin-like receptor (KIR) genotyping in allogeneic hematopoietic stem cell transplantation for myeloid disorders at our institution, retrospective KIR genotyping was performed on 77 patients and their 10/10 matched unrelated donors. In a multivariate model including donor age, HLA-DPB1 permissiveness, and presence of donor KIR B/x, an association with overall survival was observed (p = .047). Within the model, increasing donor age increased risk (RR 1.03 [1.00-1.06]/year, p = .046), while donor KIR and HLA-DPB1 permissiveness were not associated with risk (RR 0.51 [0.26-1.03] and RR 0.68 [0.34-1.36]). Grouping recipients by conditioning regimen or limiting the analysis to recipients of peripheral blood stem cells, no association between donor KIR and survival or relapse was identified. No significant associations were observed between overall survival, relapse, grade III-IV acute, or chronic graft versus host disease and presence of KIR B (B/x), quantity of donor KIR B haplotype motifs, or centromeric KIR type (all p > .05).

Clinical outcomes of HLA-DPB1 mismatches in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic stem cell transplant.

OBJECTIVE: HLA-DPB1 matching may impact allogeneic hematopoietic stem cell transplantation (ASCT) outcomes; however, this locus is not in linkage disequilibrium with the remainder of the HLA genes. After classifying HLA-DPB1 mismatches based on T-cell epitope, avoiding non-permissive mismatches may impact survival. We tested this hypothesis at a single academic institution. METHODS: Retrospective HLA-DPB1 genotyping was performed on 153 adult patients who underwent ASCT and unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 loci (10/10). Using the ImMunoGeneTics/HLA T-cell epitope matching algorithm, mismatch status was classified as permissive or non-permissive. RESULTS: Of 153 donor-recipient pairs, 22 (14.4%) were HLA-DPB1 matches, 64 (42.8%) permissive mismatches, and 67 (43.8%) non-permissive mismatches. DPB1 mismatch increased risk of chronic graft-versus-host disease (cGVHD; RR 2.89 [1.19-9.53], P=.016) compared with DPB1-matched transplants, but there were no differences in overall mortality, risk of relapse, or acute GVHD (aGVHD). Combining matches and permissive mismatches and comparing to non-permissive mismatches, there was no significant difference in overall survival or relapse; however, patients receiving non-permissive mismatched transplants experienced greater risk of aGVHD overall and severe aGVHD (RR 1.66 [1.13-2.44], P=.010 and RR 1.97 [1.10-3.59], P=.024, respectively). CONCLUSION: In this single-center study, HLA-DPB1 matching influenced outcomes of patients undergoing ASCT for hematologic malignancy.

Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet.

BACKGROUND AND AIMS: Increasingly, people start a gluten-free diet (GFD) without a clear celiac disease (CD) diagnosis. Human leukocyte antigen (HLA) genotyping is useful in ruling out CD in patients with equivocal results of serologic testing or small-bowel biopsy (SBB), but its utility and the clinical features of patients on self-treated GFD (ST-GFD) are largely unknown. METHODS: Retrospective study of single tertiary care center cohort compared 137 patients on ST-GFD and 443 patients with well-defined CD. We compared HLA genotype, symptoms, serologic and SBB results, and response to GFD between the 2 groups. Analysis used univariate logistic regression modeling, adjusted for age and sex. RESULTS: Patients with ST-GFD presented more often with diarrhea (P<0.001), abdominal distention (P<0.001), flatulence (P=0.002), cramping (P=0.02), itchy skin (P=0.02), oral inflammation (P=0.04), and constipation (P=0.01) and less often with anemia (P<0.001) or malaise (P=0.02) than CD patients. In addition, 41% did not carry DQ2.5 and DQ8 versus 6% of CD patients (P<0.001). Only 2% of ST-GFD patients had SBB clearly consistent with CD. Family history of CD showed no difference between groups (P=0.77). Although CD patients had a statistically higher rate of GFD benefit, both groups had a high responsiveness rate (98% vs. 94%; P=0.03). CONCLUSIONS: HLA genotyping is useful in evaluating patients on an ST-GFD. Although confirmed CD is rare in self-treated patients, most still report benefit from GFD regardless of DQ2 and DQ8 status. Nonceliac gluten sensitivity may play a role.

Lymphocytic duodenosis and the spectrum of celiac disease.

OBJECTIVES: Celiac disease (CD) is a chronic inflammatory disease of the small bowel that is characterized by increased intraepithelial lymphocytes (IELs) and villous atrophy of the mucosa. It is unclear how often intraepithelial lymphocytosis in the absence of atrophy is a manifestation of gluten sensitive enteropathy. The objective of this study was to identify factors that discriminate patients with CD from those with lymphocytic duodenosis (LD, intraepithelial lymphocytosis without villous atrophy). We compared Class 2 HLA type, presenting symptoms, and serology in patients with LD and CD. METHODS: Retrospective review of 124 systematically assessed patients with LD compared with 454 CD patients with villous atrophy. All patients had duodenal biopsies and Class 2 HLA typing performed. HLA type, symptoms, serology pattern, and response to a gluten-free diet were analyzed using univariate logistic regression modeling, adjusted for age and gender. RESULTS: Half of the (63 (51%)) LD patients lack the Class 2 HLA genotypes encoding DQ2 or DQ8 whereas only 11 (2%) CD patients had neither DQ2 nor DQ8, P<0.001. The genes encoding DQ2 were much more prevalent in CD (91%) than that in LD (37%, P<0.001), however, the rate of carriage of DQ8 did not differ between the two groups (15% vs. 15%, P=0.9). Although diarrhea and weight loss were equally frequent in LD and CD patients, LD patients were less likely to be associated with anemia (P=0.007), malaise (P=0.006), skin disorder (P=0.007), or a family history of CD (P<0.001). The LD subjects were much less likely to have tissue transglutaminase or endomysial antibodies than were CD subjects (12% or 0% vs. 87% and 87%; P<0.001, respectively). CONCLUSIONS: The LD cohort differs significantly in terms of HLA type, serology, and clinical features, suggesting that the majority of patients with LD do not belong in the spectrum of CD.

HLA DQ gene dosage and risk and severity of celiac disease.

BACKGROUND & AIMS: Celiac disease (CD) is a chronic inflammatory disorder of the small intestine that is strongly associated with certain HLA molecules encoded by DQA and DQB genes. The aim of this study was to examine the role of DQA and DQB alleles in determining the risk for and the age of onset and severity of CD in an American population. METHODS: High-resolution class 2 HLA genotyping was performed in a population-based sample (n = 84) of southeastern Minnesota residents with CD and a comparable control group (n = 102) to determine the contribution of DQA and DQB alleles to disease risk. Logistic regression modeling was used to examine the relative and absolute risks of CD. RESULTS: Ninety-seven percent of CD patients carried both of the HLA alleles, DQA1*05 and DQB1*02. Those who carried a second allele of DQB1*02 were 5 times more likely to have CD than those with just one (95% confidence interval, 1.4-18.1). The carriage of 2 copies of DQB1*02 did not predict either an earlier age of onset or severity of disease. CONCLUSIONS: Both HLA alleles DQA1*05 and DQB1*02 are associated with a greatly increased risk of CD, although the latter has the greater effect. Carrying 2 copies of DQB1*02 was associated with an even greater risk for disease but did not predict an earlier age of onset and diagnosis or disease severity. Assessing the copy number of the DQB1*02 allele might allow for the stratification of disease risk.