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.

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.