Quantitative Association Tests of Immune Responses to Antigens of Mycobacterium Tuberculosis: A Study of Twins in West Africa

There is now considerable evidence that host genetic factors are important in determining the outcome of infection with Mycobacterium tuberculosis (MTB). The aim of this study was to assess the role of several candidate genes in the variation observed in the immune responses to MTB antigens. In-vitro assays of T-cell proliferation, an in-vivo intradermal delayed hypersensitivity response; cytokine and antibody secretions to several mycobacterial peptide antigens were assessed in healthy, but exposed, West African twins. Candidate gene polymorphisms were typed in the NRAMP1, Vitamin D receptor, IL10, IL4, IL4 receptor and CTLA-4 genes. Variants of the loci IL10 (-1082 G/A), CTLA-4 (49 A/G) and the IL4 receptor (128 A/G) showed significant associations with immune responses to several antigens. T-cell proliferative responses and antibody responses were reduced, TNF-alpha responses were increased for subjects with the CTLA-4 G allele. The T-cell proliferative responses of subjects with IL10 GA and GG genotypes differed significantly. IL4 receptor AG and GG genotypes also showed significant differences in their T-cell proliferative responses to MTB antigens. These results yield a greater understanding of the genetic mechanisms that underlie the immune responses in tuberculosis and have implications for the design of therapeutic interventions.

Blockade of the C5a receptor fails to protect against experimental autoimmune encephalomyelitis in rats

Complement activation contributes to inflammation and tissue damage in human demyelinating diseases and in rodent models of demyelination. Inhibitors of complement activation ameliorate disease in the rat model antibody-dependent experimental autoimmune encephalomyelitis and rats unable to generate the membrane attack complex of complement develop inflammation without demyelination. The role of the highly active chemotactic and anaphylactic complement-derived peptide C5a in driving inflammation and pathology in rodent models of demyelination has been little explored. Here we have used a small molecule C5a receptor antagonist, AcF-[OPdChaWR], to examine the effects of C5a receptor blockade in rat models of brain inflammation and demyelination. C5a receptor antagonist therapy completely blocked neutrophil response to C5a in vivo but had no effect on clinical disease or resultant pathology in either inflammatory or demyelinating rat models. We conclude that C5a is not required for disease induction or perpetuation in these strongly complement-dependent disease models.

Connective tissue panniculitis in a child with vitiligo and Hashimoto's thyroiditis

A 9-year-old girl presented with a 6-month history of inflamed tender nodules in the pretibial area. These eventually healed leaving depressed areas of atrophy and loss of subcutaneous tissue. Histology showed a predominantly lymphocytic lobular panniculitis, consistent with connective tissue panniculitis. Investigations revealed an elevated thyroid stimulating hormone, elevated thyroid antiperoxidase antibody and a weakly positive antinuclear antibody (titre 1 in 40). She was commenced on hydroxychloroquine 300 mg daily, which resulted in resolution of the pannictulitis. She developed focal Vitiligo oil the thighs. This gradually improved with 0.1% mometasone furoate ointment. The hydroxychloroquine dose was tapered to 200 mg daily after 12 months, then to 100 mg daily after 18 months therapy. Her thyroid autoantibody levels continued to rise and the hydroxychloroquine was increased again to 300 mg daily. She became borderline hyothyroid. Hashimoto's thyroiditis was diagnosed. Thyroxine was instituted with a resultant improvement in her thyroid blood tests. The lipoatrophy has not developed further during 2-year follow up.