HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype.

OBJECTIVE: Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype. METHODS: Separate discovery and validation subcohorts of patients recruited from a relatively homogeneous population were studied by sequence-based HLA typing, in which frequencies of the HLA-B and HLA-C alleles and haplotypes were compared. RESULTS: In patients with psoriatic arthritis, the frequency of C*06:02 was lower than that in patients with psoriasis (28.7% versus 57.5%; P = 9.9 × 10(-12) ). Three haplotypes containing B*27:05 or B*39:01 were significantly increased in frequency in patients with psoriatic arthritis, but not in those with psoriasis. The structurally related B*39:06 allele was not increased in frequency. B*27 was associated with an interval of 0.98 years between skin and musculoskeletal disease (P = 2.05 × 10(-6) ), compared with an interval of 10.14 years for C*06. Preliminary evidence suggested that B*38:01 and B*08 may be associated with psoriatic arthritis susceptibility, and that allotypes encoding P2 pockets that bind side chains opposite in charge from those encoded by the B*27 and B*39 molecules may exert a protective role. CONCLUSION: These findings suggest that the psoriasis phenotype results from two patterns of MHC effect. The first involves the classic psoriasis susceptibility gene C*06, which confers more penetrant skin disease with less prevalent and more time-dependent musculoskeletal phenotype development. The second pattern appears to be mediated by HLA-B alleles, notably B*27, and includes temporally more coincident musculoskeletal involvement that is nearly equivalent in penetrance to that of the skin disease.

Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell ß-chain clonotypes in progressive lupus nephritis.

OBJECTIVE: To better define the immunologic character of the T cell infiltrate in lupus nephritis. METHODS: We performed double immunohistochemical staining and clonotypic T cell receptor (TCR) ß-chain sequencing in multiple anatomic regions isolated by laser-capture microdissection from renal biopsy samples. RESULTS: Systemic lupus erythematosus (SLE) kidneys have a variably patterned and often extensive infiltrate of predominantly clonally expanded T cells of CD4 and CD8 lineages. CD4+ T cells were prominent in nearly two-thirds of SLE biopsy samples and were distributed as broad periglomerular aggregates or intermixed with CD8+ T cells forming periglomerular caps. Sequencing of the TCR from periglomerular regions showed a predominance of clonally expanded T cells. The CD8+ T cells, which were present in all biopsy samples, often adhered to Bowman's capsule and infiltrated the tubular epithelium. They exhibited features that suggest participation in an adaptive immune response: differentiation into CD28(null) memory-effector phenotype, trafficking of the same expanded clonotype to different regions of the kidney and to the peripheral blood, and clonal persistence for years in repeat biopsy samples. CD8+ T cell tubulitis was especially associated with progressive changes. CONCLUSION: The immunologic characteristics of the infiltrating CD4+ and CD8+ T cells in the lupus kidney indicate that they have the potential to mediate injury, which may be relevant to development of progressive renal failure. Whereas the oligoclonality of the CD4+ T cell infiltrate is consistent with the paradigm of SLE as a class II major histocompatibility complex-associated autoimmune disease, the finding of CD8+ T cell clonality and trafficking implies participation in a distinct systemic adaptive immune response.

The genomic sequence of the accidental pathogen Legionella pneumophila.

We present the genomic sequence of Legionella pneumophila, the bacterial agent of Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes a 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions of important gene families, genes for unexpected metabolic pathways, and previously unknown candidate virulence determinants. We highlight the genes that may account for Legionella's ability to survive in protozoa, mammalian macrophages, and inhospitable environmental niches and that may define new therapeutic targets.