Franco Papola

Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes.

Guillain-Barré syndrome (GBS) is the prototype of a postinfectious autoimmune neuropathy. Molecular mimicry between glycolipid antigens expressed by an infective antigen such as Campylobacter jejuni and the human peripheral nerve has been hypothesized to be the causative mechanism of GBS. However, only 1/1000 of C. jejuni enteritis develops GBS. This emphasizes the importance of host-related factors in the development of the disease. HLA studies in GBS failed to show an association or gave conflicting results but MHC class I and II process and present peptides to T lymphocytes making unlikely that the HLA system plays a role in GBS with autoantibodies against self-gangliosides. CD1 molecules are MCH-like glycoproteins specialized in capturing and presenting a variety of glycolipid to antigen-specific T cells. There are five closely linked CD1 genes in humans located in chromosome 1 (named CD1A, B, C, D, and E) all showing limited polymorphism in exon 2 which codifies for the alpha1 domain of CD1 molecules. The nucleotide substitutions in CD1B and CD1C are rare and reported to be silent. In 100 controls and 65 GBS patients (21 with a recent C. jejuni infection and 35 with anti-glycolipid antibodies) we used direct sequencing by polymerase chain reaction to genotype exon 2 of CD1A, CD1D and CD1E genes. CD1D is monomorphic in both controls and patients whereas CD1A and CD1E are biallelic in exon 2. Subjects with CD1E*01/01 genotype are 2.5 times more likely to develop GBS, whereas subjects with CD1A*01/02 or CD1E*01/02 have a reduced relative risk by 3.6 and 2.3 times respectively. The combination of CD1A*01/02 and CD1E*01/02 reduces by 5 times the risk of developing GBS. Although a correlation between CD1E*01/01 genotype and recent C. jejuni infection or presence of antiganglioside antibodies was not found the overall findings indicate that susceptibility to develop GBS is associated with polymorphisms of CD1E and CD1A genes.

HLA typing does not predict REM sleep behaviour disorder and hallucinations in Parkinson's disease.

HLA‐DR2 haplotype and DQ1 DNA alleles, characterizing 90 to 100% of all narcoleptic patients, were found to be equally distributed in 20 Parkinsons disease (PD) patients with early hallucinations, rapid eye movement (REM) sleep‐related behaviour disturbances (RBD), and sleep onset in REM (SOREM), and in 20 PD patients without hallucinations, despite 10 to 15 years of treatment, and no RBD or SOREM.

HLA DR/DQ alleles and risk of type I diabetes in childhood: a population–based case–control study

AbstractThe objective was to evaluate HLA DR/DQ alleles and their risk factor for type 1 diabetes in the Abruzzo region (central Italy). Sixty incident cases from the Abruzzo region were studied together with 120 unrelated control subjects living in the same administrative areas. The relative risk of diabetes associated with the alleles under study was calculated by deriving the odds ratio (OR) maximum likelihood estimates and their 95% confidence intervals (CI) by the exponentiation of the logistic regression beta–parameter. The combination DRB1*03/DQA1*0501/DQB1*0201 was found in 20.0% of patients and 7.1% of the control subjects, conferring an OR of 4.04 and a CI of 1.97–8.49. The combination DRB1*04/DQA1*0301/DQB1*0302 was found in 23.3% of diabetic patients and 6.7% of controls, giving an OR of 5.69 and a CI of 2.77–12.05. DRB1*11/DQA1*0505/DQB1*0301 and DQA1*0505/DQB1*0301 were negatively associated with type 1 diabetes (OR=0.27, CI 0.11–0.57; OR=0.07, CI 0.02–0.19). The DQA1 genotype at risk was found to be DQA1*0301/DQA1*0501: OR=23.80, CI 2.97–190.89, as it occurred with the highest frequency in the patient group. The DQB1 genotype at risk was found to be DQB1*0201/DQB1*0302, which occurred in 13.3% of patients but in only 1.1% of the control group (OR=29.75, CI 5.36–549.25). Our results shed further light on the risk of development of this disease during a specific time period in an area where the overall incidence of type 1 diabetes is known.

A new HLA-A allele identified in a leukemic patient attending hematopoietic cell transplantation: A*2318.

Sequence-based typing procedure (SBT) procedure permitted us to identify a new human leukocyte antigen-A allele in a patient attending hematopoietic stem cell transplantation.

HLA‐DRB1*13:01 allele in the genetic susceptibility to colorectal carcinoma

Increasing evidence suggests that HLA‐DRB1 alleles reduce or increase the risk of developing ulcerative colitis‐associated colorectal carcinoma (CRC) tumors. However, the role of HLA‐DRB1 locus on the susceptibility to develop CRC tumor, in the absence of a history of inflammatory bowel diseases (IBDs), is unclear. The aim of our study was to determine whether HLA‐DRB1 alleles are associated with IBD‐independent CRC tumor. HLA‐DRB1 allele polymorphisms were identified by sequence‐based typing method in 53 CRC patients and 57 sex‐ and age‐matched healthy Caucasian controls. Pearsons chi‐squared analysis with Yates correction or Fishers exact test with Bonferronis correction, as appropriate, were used to compare the allele frequency (AF) differences of HLA‐DRB1 in patients and controls. A total of 29 HLA‐DRB1 alleles were recognized. A detailed study of these alleles allowed to identify DRB1*13:01 and DRB1*11:01 alleles that were significantly associated with an increased and reduced risk to develop CRC tumor, respectively. AF of DRB1*13:01, in CRC patients, was significantly higher than that of healthy controls, even following Bonferronis correction (p = 0.029). In contrast, the presence of the DRB1*11:01 allele was negatively associated with CRC tumor as evidenced by the significantly lower AF in CRC patients than that of healthy controls (p = 0.005). However, following Bonferronis correction, the AF of DRB*11:01 lost its statistical significance. These results suggest that HLA‐DRB1*13:01 allele could be a potential marker for predicting genetic susceptibility to CRC tumor. In contrast, the protective role of DRB1*11:01 remains unclear.

704 Local expression of cytokines in human colorectal carcinoma

Cytokines locally expressed in cancer may regulate anticancer response and could be autocrine growth stimulators. To characterize the local immune situation in colorectal cancer, constitutive expression of cytokine mRNAs has been investigated in tumor specimens (central and peripheral), normal mucosa and peripheral blood mononuclear cells (PBMC) in 12 patients underwent surgical resection. mRNA for interleukin (IL)2, IL-4, IL-6, IL-IO, IL-2R (p55), CD3, and β-actin as positive control was detected by reverse transcriptase-polymerase chain reaction (RTPCR) technique, using 1 μg of total RNA for reverse transcription and 28 or 30 cycles of cDNA amplification with specific primer pairs. Results 70% of cases constitutively expressed mRNA for IL-6 in tumor tissues but not in normal mucosa; only in one case IL-6 was expressed both in tumor and in normal mucosa. mRNA for IL-2R (p55) was found in 50% of tumors and in no specimen of normal mucosa. No expression of IL-2 and IL-4 mRNAs was detected at local site. IL-10 was variably expressed at low levels in tumors, normal mucosa and PBMC. CD3 expression was not associated with differences in cytokine gene expression. These findings may be relevant for better understanding the role of cytokines at the tumor site. IL-6 is known to be involved in cancer proliferation as an autocrine stimulator: it seems that oncogenes and oncosuppressor genes are involved in the modulation of its expression in some neoplasms. The present study will be also developed in this direction. Supported by: C.N.R. Targeted Project “ACRO”.