Multiple sclerosis risk markers in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific childhood leukemia risk.

Previous epidemiologic studies showed four times increased risk of acute lymphoblastic leukemia (ALL) in children of women with multiple sclerosis (MS). MS shows a risk association with Human leukocyte antigens (HLA)-DRA single nucleotide polymorphism (SNP) rs3135388, which is a proxy marker for DRB1*1501. We examined the relevance of rs3135388 in childhood ALL risk along with two other HLA-DRA SNPs in two case-control groups: 114 cases and 388 controls from South Wales (UK) and 100 Mexican Mestizo cases and 253 controls. We first confirmed the correlation between rs3135388 and DRB1*1501 in HLA-typed reference cell lines. We noted a female-specific risk association in childhood ALL (pooled odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.5-4.5, Mantel-Haenszel P = 0.0009) similar to the stronger association of DRB1*1501 in females with MS. Examination of an HLA-C 5' flanking region SNP rs9264942, known to correlate with HLA-C expression, showed a protective association in girls (OR = 0.4, 95% CI = 0.2-0.7, Mantel-Haenszel P = 0.0003) similar to the protective HLA-Cw*05 association in MS. In a reference cell line panel, HLA-Cw5 homozygous samples (n = 8) were also homozygous for the minor allele of the SNP. Likewise, the male-specific protective association of interferon-gamma (IFNG) SNP rs2069727 in MS was replicated with the same sex specificity in childhood ALL (OR = 0.6, 95% CI = 0.4-1.0, Mantel-Haenszel P = 0.03). Two other SNPs in superkiller viralicidic activity 2-like and tenascin XB that are markers for systemic lupus erythematosus susceptibility showed female-specific associations but due to linkage disequilibrium with HLA-DRB1*15. Our observations supported the epidemiologic link between MS and childhood ALL and added the sex effect to this connection. It appears that only girls born to mothers with MS may have an increased risk of ALL. Investigating the mechanism of these sex-specific associations may help understand the pathogenesis of MS and ALL.

Hematopoietic stem cell transplantation (HSCT): an approach to autoimmunity.

HSCT provides the opportunity to replace a damaged tissue. It is the most important treatment for high risk hematologic malignant and non malignant disorders. An important challenge in the identification of matched donors/patients is the HLA diversity. The Mexican Bone Marrow Registry (DONORMO) has nowadays > 5000 donors. The prevalent alleles are Amerindian, Mediterranean (Semitic and Spanish genes) and African. In theory, it is possible to find 11% of 6/6 A-B-DR low resolution matches for 70% of patients with Mexican ancestry. We contributed with 39 unrelated, cord blood and autologous HSCT for patients with malignant, genetic and autoimmune disorders. Overall disease survival was 50% (2-7 years) depending on the initial diagnosis, conditioning, disease evolution or other factors. Clinical studies using autologous and unrelated HSC are performed on patients with refractory autoimmune diseases producing mixed results: mainly, T1D, RA, MS, SLE. Improvement has been observed in skin damage and quality of life in SLE and systemic sclerosis. Disease stabilization in 2/3 of MS patients. However, in RA and T1D, initial benefits have been followed by eventual relapse. With growing clinical experience and protocol improvement, treatment-related mortality is decreasing. Proof efficacy will be achieved by comparing HSCT with standard therapy in autoimmunity.

HLA and autoimmune diseases: Type 1 diabetes (T1D) as an example.

Autoimmune diseases need to be considered at a genetic and mechanistic level. T1D is an autoimmune, chronic, multifactorial and polygenic disease characterized by the destruction of the pancreatic beta-cells associated with long term dysfunction of several organs and tissues. Mechanisms of susceptibility include epi-genetic and post-transcriptional effects that regulate transmission and expression of the inherited genes. The HLA complex, constitutes the most relevant region contributing 50% of the inherited risk for T1D. An additional 17 genes with variable but small effects have been described. In non-Caucasians, the presence of E-DRbeta1-74 and/or D-DRbeta1-57 are relevant in predisposition. The "Diabetogenic haplotypes" in Mexicans were DRB1*0301-DQA1*0501-DQB1*0201 (OR = 21.4); DRB1*0405-DQA1-*0301-DQB1*0302 (OR = 44.5) and the same DQA1/DQB1 with DRB1*0404/*0401 conferring lower risk, increasing (OR = 61.3) with an early age at onset and a heterozygote DR3/DR4 genotype. In most populations, the absence of D-57 and the presence of R-52 are important to the susceptibility, but in Hispanics, all DR4s (including the protective DRB1*0403/*0407/*0411) are in linkage disequilibrium with DQA1/DQB1 susceptibility alleles. Thus, susceptibility alleles in Latin American Mestizos are of Mediterranean ancestry whereas protective alleles are of Amerindian origin. In this review, we discuss the complexity of T1D and some aspects of prevention/intervention based on immunogenetics.

Classic Pars Planitis: strong correlation of class II genes with gender and some clinical features in Mexican Mestizos.

The purpose of this study was the investigation of human leukocyte antigen (HLA) genes in Mexicans with classical Pars Planitis (CPP). Seventy-nine unrelated patients and 204 healthy controls were studied. HLA-A, -B, and -C typing was done on T cells isolated with immunomagnetic beads. HLA-DRB1, -DQA1, and -DQB1 loci were typed by polymerase chain reaction-sequence-specific oligonucleotide probes. The significance and strength of HLA associations were assessed. Stratification analyses were performed to analyze correlations between HLA alleles and clinical manifestations or gender. The mean age of CPP patients was 10 years old. The disease was recurrent (21.3%); 58% were males and 89.6% were bilaterally affected. A 3-year follow-up demonstrated no other associated disease. DRB1*0802 was significantly increased (odds ratio [OR] = 2.8, etiologic fraction [EF] = 18.96%). In females, HLA-B51 (OR = 9.8) was associated with nonsymmetrical onset and HLA-Cw1 (OR = 4.7) with symmetrical onset; DRB1*0802 was increased in males (OR = 3.9, p =5.0 E-05, EF = 38.3%) and contributed to their symmetrical onset (OR = 4.6, p =4.6 E-06, EF = 29.4%). Corneal peripheral endotheliopathy correlated with DQB1*0602 in females (OR = 17, EF = 47.1%). A susceptibility allele of Amerindian ancestry is responsible for juvenile CPP in Mexicans; HLA-B locus contributes to severity in females and DRB1*0802 in males. CPP should be classified as an heterogeneous illness taking into account ethnicity, and clinical and genetic characteristics.