The clinical features of ankylosing spondylitis ( A S ) were compared in 63 HLA-B 27 positive ( + ) and 15 B27 negative ( -) individuals with this disease. There were no differences in age at onset, functional class, degree of deformity, pain, severity of X-ray changes, or frequency of peripheral joint involvement or of reconstructive orthopedic surgery. These data demonstrated that skeletal manifestations of AS were essentially the same in B27( +) and ( -) patients, and provide no evidence for the speculation that AS in B27( -) patients is milder or is a different disease from that occurring in B27(+) patients. On the other hand, acute anterior uveitis was found to be significantly more common in B27( +) patients, a fact suggesting that the "uveitis of AS" may in fact be an independent condition occurring in B27( +) individuals, rather than a manifestation of A S per se.The association between ankylosing spondylitis (AS) and the presence of HLA-B27 is remarkably strong

BackgroundHuman natural killer (NK) cell activity is regulated by a family of killer cell immunoglobulin-like receptors (KIRs) that bind human leukocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes.ResultsThe impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding.ConclusionKIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, providing an explanation for KIR2DL3–C1 interactions appearing weaker than KIR2DL1–C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR–HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition.

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Objective. Systemic lupus erythematosus (SLE) develops much more readily in females than in males. Previous research has focused primarily on identifying mechanisms pertinent to the pathology in females. The aim of the current study was to delineate active protective mechanisms in males. We present evidence of a new male-associated mechanism of protection against the development of lupus-like disease in lupus-prone (NZB ؋ NZW)F1 mice.Methods. We identified previously uncharacterized cellular and functional differences in myeloid cells between male and female (NZB ؋ NZW)F1 mice, with the use of flow cytometry, confocal imaging, in vivo antibody-mediated depletion, and in vitro cell coculture assays.Results. A population of Gr-1 high Ly-6G؉CD11b؉ myeloid cells was found to be constitutively increased in male (NZB ؋ NZW)F1 mice as compared with female mice and was regulated by testosterone. The cells were located adjacent to spleen B cell follicles in vivo and were found to directly inhibit cytokine-induced differentiation of naive B cells into antibody-secreting cells in vitro. Most notably, treatment with anti-Gr-1-depleting antibodies increased the spontaneous production of antinuclear autoantibodies in male (NZB ؋ NZW)F1 mice, while a similar approach in female mice had no effect on disease development. Conclusion. Male lupus-prone (NZB ؋ NZW)F1mice harbor elevated levels of a population of myeloid cells with pronounced immunosuppressive capacities that specifically target B cells and the production of antibodies in vivo. We suggest that these cells represent a male-driven inhibitory mechanism involved in the control of B cell pathogenesis, delaying (or preventing) lupus-like disease development in otherwise genetically predisposed male (NZB ؋ NZW)F1 mice.Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disorder. The disease is characterized by elevated levels of antinuclear antibodies (ANAs) and cellular infiltration of various organs, including the skin, heart, and kidney (1). Like most systemic autoimmune diseases, SLE predominantly affects women. The female-to-male ratio of newly diagnosed patients reaches 9:1 between the ages of 15 years and 45 years (2,3). This coincides with the years when female sex hormones are the most active, and thus, much research has focused on elucidating the role of female sex hormones (particularly estrogen) in SLE. For example, it is well accepted that elevated levels of estrogens affect B lymphocyte selection processes by altering the threshold for negative selection, thereby allowing more self-reactive B cells to survive and differentiate (4,5). Testosterone, on the other hand, is believed to be protective, based on mouse studies (6-9) and clinical data from SLE patients treated with testosterone or the adrenal steroid dehydroepiandrosterone (10-12). Still, the target of regulation and the specific mechanism of protection mediated by testosterone remain unidentified.In some animal models of SLE, female predominance is similarly observed. One such mode...

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Background. Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys 80 ) and KIR2DL2 and KIR2DL3 bind

Objectives: The objectives were to identify factors that may help predict mortality for patients with delirium tremens (DT). Methods:The authors conducted a 1:1 gender-and age-matched case-control study of patients hospitalized for DT. Using McNemar chi-square tests and conditional logistic regression (CLR), risk factors for death, including demographics, location of diagnosis, vital sign derangements, treatment methods, and comorbid conditions, were evaluated. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) are reported.Results: Thirty-five patients with DT died between January 2000 and June 2006. The majority (31; 88.6%) were male with a mean (±standard deviation [SD]) age of 51.7 (±7.6) years. Hyperthermia in the first 24 hours of DT diagnosis (OR = 10.0, 95% CI = 2.3 to 42.7), persistent tachycardia (OR = 24.0, 95% CI = 3.3 to 177.4), and use of restraints (OR = 7.50, 95% CI = 1.7 to 32.8) were associated with increased mortality by univariate analysis, while an emergency department (ED) diagnosis of DT (OR = 0.18, 95% CI = 0.05 to 0.6) and use of clonidine (OR = 0.10, 95% CI = 0.01 to 0.78) were associated with decreased mortality. In the CLR model, restraint use and hyperthermia were the only variables that remained significant (OR = 5.8, 95% CI = 1.0 to 32.2; and OR = 6.1, 95% CI = 1.2 to 30.4, respectively). Conclusions:The use of restraints and hyperthermia is associated with increased odds of death for patients with DT. This study highlights the need for further research into modifiable factors influencing mortality from DT.ACADEMIC EMERGENCY MEDICINE 2008; 15:788-790 ª

Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1β and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1β and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.