The Involvement of HLA Class II Alleles in Multiple Sclerosis: A Systematic Review with Meta-analysis.

Multiple Sclerosis (MS) displays a heterogeneous clinical onset and progression, which are mostly unpredictable, but demyelination of the central nervous system (CNS) leads to substantial deficits of sensory, motor, autonomic, and neurocognitive functions. Considering all genetic studies on MS, including the advanced genome-wide association studies, the risk linked to HLA alleles remains the highest among other susceptibility genetic variants. However, given the genetic variability of HLA alleles in different ethnic groups, we conducted a systematic review of reviews and meta-analyses aiming at summarizing all the results on the association between MS and HLA class II genes. We systematically searched meta-analyses and systematic reviews dealing with MS and HLA in all ethnicities. From 154 records, we included 5 articles collecting HLA data from 15,232 MS patients and 24,194 ethnically matched controls. DRB1∗15 (OR ranging from 1.39 in Chinese Han to 2.59 in Caucasians) and DQB1∗06:02 (OR ranging from 1.91 in Caucasians to 2.49 in Colombian) alleles confer an increased risk for MS transethnically (Caucasians, Chinese, South Americans, Carribeans, Middle Easterners, Japanese, and North Africans). DRB1∗01, DRB1∗09, DRB1∗11, DRB1∗12, and DRB1∗16 alleles were protective, in agreement with the type of amino-acidic (aa) residues (ranging from position 9 to 90) included in pockets 1, 4, 6, 7, and 9, which are most involved in peptide presentation. Changes in aa residues affect the capability of HLA molecules in binding myelin peptides. DQB1∗06:02 risk allele seems to be the most interesting target as humanized mice expressing only DQB1∗06:02 develop MS-like disease mediated by autoimmune reactions against myelin oligodendrocytic basic protein that stabilizes the myelin. Our summary of results from a high number of patients and controls suggests that allelic variants from both DQB1 and DRB1 genes are equally involved in MS susceptibility/protection transethnically.

Correlation between HLA-DQB1*06:02 and narcolepsy with and without cataplexy: approving a safe and sensitive genetic test in four major ethnic groups. A systematic meta-analysis.

STUDY OBJECTIVES: we performed a meta-analysis to assess the usefulness of HLA testing for Narcolepsy diagnosis in four major ethnical groups: Asians, Afro-Americans, Amerindians and Caucasians. METHODS: PubMed, EMBASE, Web of Science, Scopus and Cochrane databases were searched for articles in English and French published before October 2017 on HLA class II alleles in Narcolepsy. We included case-control studies, cross-sectional and retrospective cohort studies with patients diagnosed following the International classifications of sleep disorders (1990-2012) and ethnically matched controls. Following PRISMA guidelines, two investigators independently extracted data according to the inclusion criteria listed in PROSPERO CRD42017058677. A third researcher was consulted for discrepancies. We extracted and pooled adjusted OR using random-effect models. We verified the strength of the association between HLA-DQB1*06:02 and the worldwide distribution of Narcolepsy type 1 (NT1) and type 2 (NT2); furthermore, we pooled the OR measuring the association between HLA-DQB1*06:02 and NT1, NT2 and hypersomniacs. RESULTS: We identified 511 titles. Of these, 12 case-control studies were included, for a total of 2077 NT1 patients, 235 NT2 patients, 161 hypersomniacs and 7802 controls. In the population-stratified analysis, HLA-DQB1*06:02 conferred an increased risk for NT1 (OR: 24.1, IC: 14.6-39.5, p < 0.001) and NT2 (OR: 3.9; IC: 2.2-6.8, p < 0.001). For NT1 the pooled estimated positive Likelihood Ratio (LR+) was 5.94 (IC: 3.71-9.51) and the negative Likelihood Ratio (LR-) was 0.23 (IC: 0.16-0.33); for NT2 LR+ was 3.35 (IC: 2.08-5.38) and LR- 0.72 (IC: 0.63-0.81). Moreover, for hypersomniacs LR+ was 1.436 (IC 0.668-3.089) and LR- 0.903 (IC 0.714-1.142). CONCLUSIONS: Our data support the preponderant role of HLA-DQB1*06:02 in susceptibility to NT1/NT2 across all ethnicities. HLA-DQB1*06:02 negativity should make clinicians cautious in excluding other diagnoses.

Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility.

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

The distribution of KIR-HLA functional blocks is different from north to south of Italy.

The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.

Targeting the immunogenetic diseases with the appropriate HLA molecular typing: critical appraisal on 2666 patients typed in one single centre.

We compared the immunogenetic data from 2666 patients affected by HLA-related autoimmune diseases with those from 4389 ethnically matched controls (3157 cord blood donors CBD, 1232 adult bone marrow donors BMD), to verify the appropriateness of HLA typing requests received in the past decade. The frequency of HLA-B∗27 phenotype was 10.50% in 724 ankylosing spondylitis, 16.80% in 125 uveitis (3.41% BMD, 4.24% CBD, P < 0.0001); HLA-B∗51 allele was 15.57% in 212 Behçet's disease (12.91% BMD, 9.88% CBD, P < 0.0001); the HLA-DRB1-rheumatoid arthritis (RA) shared epitope was 13.72% in 554 RA (10.85% BMD, 13.48% CBD, P = 0.016); the carriers of almost one of HLA-DQB1 susceptibility alleles were 84.91% in 795 celiac disease (CD) and 59.37% in 256 insulin-dependent diabetes mellitus (IDDM) (46.06% in 875 CBD, 42.75% in 662 BMD P < 0.0001). Overall, our results show that the HLA marker frequencies were higher in patients than controls, but lower than expected from the literature data (excluding CD and IDDM) and demonstrate that, in complex immunogenetic conditions, a substantial number of genetic analyses are redundant and inappropriate, burdening to the public health costs. For this reason, we suggest the Italian Scientific Society of Immunogenetics to establish guidelines to improve the appropriateness of typing requests.

Possible KIR-driven genetic pressure on the genesis and maintenance of specific HLA-A,B haplotypes as functional genetic blocks.

The HLA genomic structure underlines the permanence of fixed haplotypes transmitted in blocks as allelic combinations. One of the most discussed concerns is how and why such a strong linkage between HLA alleles has been maintained for so long. We hypothesized a possible KIR-driven pressure in the genesis of specific HLA-A,B haplotypes. Certain HLA-A and -B molecules are ligands for the same KIR receptors through the Bw4 binding motif spanning residues 77-83 in the α1 domain. We analyzed the HLA-A and -B genomic types of 9897 Caucasian people (3533 newborns and 6364 adults) subdividing them according to the presence/absence of the HLA-B Bw4 serological epitope. For each HLA-B Bw4- and Bw6-cross-reactive group, we evaluated the presence/absence of HLA-A ligands for KIR3DL1 (HLA-A*23, HLA-A*24, HLA-A*32) and KIR3DL2 (HLA-A*03, HLA-A*11). The frequency of HLA-A KIR ligands significantly increased moving from the HLA-B Bw4/Bw4 to the HLA-B Bw4/Bw6 and the HLA-B Bw6/Bw6 groups among both newborns and adults (P<0.0001). Here, we suggest that, when the HLA-B KIR-ligand motif is lacking, the HLA-A KIR-ligand might have a vicarious role in controlling the natural killer cell-mediated innate immune response. Basing upon this compensatory function in the engagement of KIR receptors, we hypothesize that specific HLA-A,B ancestral haplotypes were generated.

Birth-weight as a risk factor for cancer in adulthood: the stem cell perspective.

The 'stem cell burden' hypothesis represents a plausible explanation for the association between birth-weight and the risk of breast cancer in adulthood. The size of the overall stem cell pool would be expected to affect organ size and consequently birth-weight, making birth-weight a proxy for the overall number of fetal stem cells. As stem cells are self-renewing, the greater their number is at birth, the higher will be the chance that one of them will undergo carcinogenesis over the years. To investigate the correlation between birth-weight and stem cell burden, we examined the cord blood hematopoietic CD34+ stem cell population as an indicator of the overall fetal stem cell number. We measured both the CD34+ level (by flow cytometry) and the CD34+ proliferative potential (by the GM-CFU culture), in a sample of 1037 healthy newborn cord blood donors. We found that heavier babies had a significantly greater CD34+ stem cell concentration (p<0.001) and a higher GM-CFU number than lighter babies (p<0.001). Thus, a high birth-weight was positively associated with a high concentration of CD34+ stem cells and also with a qualitatively higher "stemness" of this pool. Therefore, our data support the theory that birth-weight reflects the number of fetal stem cells.

HLA haplotypes and birth weight variation: is your future going to be light or heavy?

Birth weight is known to be a direct indicator of perinatal mortality and a clear predictor of adult pathologies too. It has been correlated with several causes of mortality in adulthood: low birth weight with diabetes, nephropathy and cardiovascular diseases and high birth weight with autoimmune diseases and cancer. In genome-wide studies, an extended human leucocyte antigen (HLA) region has been linked to birth weight variation. We focused our attention on the HLA haplotypes marked by HLA-A, HLA-B and HLA-DRB1 polymorphisms in 1206 healthy Caucasian newborns belonging to the Cord Blood Bank of Pavia (Italy) and their mothers, aiming to investigate the association between this restricted HLA region and birth weight variation. In our study, the HLA-B*38;DRB1*13 haplotype showed an ascending trend among centiles addressing to the high foetal weight. The HLA-A*02;B*15 haplotype showed a descending trend among centiles addressing to the low foetal weight. Besides the acknowledged correlation between the HLA-A*02 and HLA-B*15 alleles (as well as low birth weight) and type I diabetes and between the HLA-B*38 and HLA-DRB1*13 alleles (as well as high birth weight) and several autoimmune diseases, we cannot predict if our babies, healthy at birth, will suffer from these pathologies during life. Nevertheless, our data point to the HLA telomeric end for markers linked to the low birth weight and to the HLA centromeric end for markers linked to the high birth weight, thus limiting the region involved in birth weight variation, which still represents a useful predictor of disease risk in adulthood.