HLA-Matched Unrelated Donors for Patients with Sickle Cell Disease: Results of International Donor Searches.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Hematopoietic stem cell transplantation (HCT) is the sole curative therapy for SCD, but few patients will have a matched sibling donor. Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries. Using HaploStats, we estimated HLA haplotypes for 185 patients with SCD (116 from a Brazilian center and 69 from European Society for Blood and Marrow Transplantation [EBMT] centers) and classified the ethnic origin of haplotypes. Then we assessed the probability of finding an HLA-matched unrelated adult donor (MUD), considering loci A, B, and DRB1 (6/6), in international registries. Most haplotypes were African, but Brazilians showed a greater ethnic admixture than EBMT patients. Nevertheless, the chance of finding at least one 6/6 potential allelic donor was 47% for both groups. Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry. Although the probability of finding a donor is higher than previously reported, strategies are needed to improve ethnic diversity in registries. Moreover, predicting the likelihood of having an MUD might influence SCD management.

The distribution of HLA haplotypes in the ethnic groups that make up the Brazilian Bone Marrow Volunteer Donor Registry (REDOME).

The Registries of Bone Marrow Donors around the world include more than 30 million volunteer donors from 57 different countries, and were responsible for over 17,000 hematopoietic stem cell transplants in 2016. The Brazilian Bone Marrow Volunteer Donor Registry (REDOME) was established in 1993 and is the third largest registry in the world with more than 4.3 million donors. We characterized HLA allele and haplotypes frequencies from REDOME comparing them with the donor self-reported race group classification. Five-locus haplotype frequencies (A~C~B~DRB1~DQB1) were estimated for each of the six race groups, resolving phase and allelic ambiguity using the expectation-maximization (EM) algorithm. The top 100 haplotypes in the race groups were separated into eight clusters of haplotypes, based on haplotype similarity, using CLUTO. We present HLA allele and haplotype frequency data from six race groups from 2,938,259 individuals from REDOME. The most frequent haplotype was the same for all groups: A*01:01g~C*07:01g~B*08:01g~DRB1*03:01g~DQB1*02:01g. Some frequent haplotypes such as A*02:01g~C*16:01g~B*44:03~DRB1*07:01g~DQB1*02:01g was not found in people with Preta (Sub-Saharan African descent). A cluster including Branca (European) and Parda or non-informed (admixed) could be distinguished from both Preta (SubSaharan) and Indígena (Amerindian) groups, and from the Amarela (Asian) ones, which clustered with their original population. These results have implications on cross-population matching and can help in donor searches and population-based recruitment strategies.

Association of HLA Alleles and HLA Haplotypes with Psoriasis, Psoriatic Arthritis and Disease Severity in a Miscegenated Population.

BACKGROUND: The study of HLA classes I and II in Brazilian psoriasis patients may contribute to a better understanding of their association with the disease. OBJECTIVE: To describe HLA classes I and II of Brazilian patients with psoriasis, with or without arthritis, compare them to controls and correlate HLA markers with epidemiological and evolutional aspects of psoriasis. METHODS: A total of 55 patients with more than 5 years of psoriasis, with or without arthritis, answered a questionnaire on ethnic background and disease severity. A total of 134 bone marrow donors were controls. HLA class I and II genotyping was determined by PCR-SSP. RESULTS: Mean age was 42.4 years; 23 women and 32 men. HLA-B*57 was present in 23.6% patients and in 7.5% controls (p=0.00200, OR= 3.8381), and HLA-C*06 in 29.1% patients and in 16.4% controls (p= 0.04832, OR=2.0886). HLA-B*57 and HLA-C*18 were significantly present in patients with arthritis (p=0.00104, OR=6.6769 and p=0.00269, OR=16.50, respectively). HLA-B*57 was significantly present in patients with history of erythroderma (p=0.00548, OR= 5.1059), as was HLA-C*06 (p=0.02158, OR=3.0545). HLA-B*57 was also frequent in patients with history of hospital internment due to psoriasis (p= 0.00094, OR=7.8909) and in the ones with history of systemic treatment for psoriasis (p= 0.00011, OR= 5.3733). Haplotype HLA-A*02 B*57 C*06 DRB1*07DQB1*03 was the most common among the patients (p= 0.00069, OR= 3.528). CONCLUSION: HLA-B*57 and HLA-C*06 were significantly increased in the patients indicating risk for psoriasis. HLA-B*57 remained high in patients with history of erythroderma, hospital internment, systemic treatment, and psoriatic arthritis, showing association with disease severity. HLA-C*18 was significantly high only in patients with psoriatic arthritis. HLA-B*57 and HLA-C*06 and haplotype HLA-A*02B*57Cw*06DRB1*07 DQB1*03 seen in this study were already described before, associated with psoriasis. HLA-Cw*18 was not described in other populations in association with psoriasis.

Ccn2/Ctgf overexpression induced by cigarette smoke during cutaneous wound healing is strain dependent.

Cigarette smoke has been associated with poor healing in several studies, but the precise mechanisms involving this impairment are still not elucidated. The aim of this work was to investigate cigarette smoke exposure effects on initial phases of cutaneous healing in mice, focusing mainly on gene expression of two molecules involved in wound repair (Ccn2/Ctgf and Tgfb1) and to study if these effects are strain dependent. Mice were exposed to the smoke of nine cigarettes per day, three times per day, for ten days. In the eleventh day an excisional wound was made. The control group was sham-exposed. The cigarette smoke exposure protocol was performed until euthanasia, seven days after wounding. Wound contraction was evaluated. Sections were stained with hematoxylin-eosin, Sirius red, and toluidine blue, and also immunostained for alpha-smooth muscle actin. Gene expression of Ccn2/Ctgf and Tgfb1 was evaluated by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Smoke-exposed animals presented delay in wound contraction; fibroblastic, inflammatory, and mast cell recruitment; re-epithelialization; myofibroblastic differentiation; and Ccn2/Ctgf and Tgfb1 gene expression. Those alterations were strain dependent. This work confirmed the deleterious effects of cigarette smoke exposure on mouse cutaneous healing depending on mouse strain and links these effects to an overexpression of Ccn2/Ctgf.