Association between self-reported motivation to quit smoking with effectiveness of smoking cessation intervention among patients hospitalized for acute coronary syndromes in Switzerland.

Guidelines recommend brief smoking cessation interventions for hospitalized smokers reporting low motivation-to-quit. However, an intensive smoking cessation intervention may improve smoking cessation for these smokers. We conducted a secondary analysis of a pre-post interventional study that tested the efficacy of a proactive approach systematically offering intensive smoking cessation intervention to all hospitalized smokers with acute coronary syndrome (ACS) compared to a reactive approach offering it only to smokers willing to quit. We analyzed data from one study site in Switzerland, which recorded motivation-to-quit smoking at study inclusion between 08.2009 and 02.2012. The primary outcome was smoking cessation at 1- and 5-year. We tested for interaction by participant's motivation-to-quit score (low vs. high motivation), and calculated multivariable adjusted risk ratios (RR), stratified by motivation score. We obtained motivation scores for 230 smokers. Follow-up was 94% (217/230) at 1-year and 68% (156/230) at 5-year. Among participants with low motivation to quit, 19% of smokers in the reactive phase had quit at 1 year compared to 50% of smokers in the proactive phase (multivariable adjusted RR = 2.85, 95%CI:0.91-8.91). Among highly motivated smokers, rates did not differ between phases: 48% vs. 49% (multivariable adjusted RR = 1.02, 95%CI:0.75-1.39, p-value for interaction between motivation-to-quit categories = 0.10). At 5-year follow-up, the point estimates were similar. While our study has limitations inherent to the study design and sample size, we found that a proactive approach to offer systematic smoking cessation counseling for smokers with ACS reporting low motivation to quit was associated with higher smoking cessation rates at 1 year.

A murine Ig light chain transgene reveals IGKV3 gene contributions to anti-collagen types IV and II specificities.

A subset of autoimmune diseases result from autoantibodies targeting epitopes on matrix collagen. The most extensively studied are anti-glomerular basement membrane glomerulonephritis (or its systemic counterpart Goodpasture's disease) that destroys kidneys and lungs, and rheumatoid arthritis that leads to disabling arthritis. Autoantibodies in these disorders bind evolutionarily conserved conformational epitopes on the noncollagenous domain 1 (NC1) of the alpha3 chain of type IV [alpha3(IV)NC1] collagen in glomerular and alveolar basement membranes, and on native or citrullinated type II collagen (CII) in joint cartilage, respectively. The genetic origins of pathogenic anti-collagen B cells in these diseases is unknown, but observations from murine models raise the possibility that they overlap despite distinct in vivo immunopathologies. Monoclonal autoantibodies isolated from mice immunized with alpha3(IV)NC1 collagen or CII show a biased use of Ig light chains (LC) encoded by genes of the IGKV3 subgroup (previously Vk21 family), paired with diverse Ig heavy chains. To further explore this relationship and determine if a single murine IGKV3 LC independently predisposes to both anti-collagen responses, we generated a novel transgenic (Tg) C57BL/6 mouse that expresses a productively rearranged IGKV3-encoded LC, termed mLCV3-Tg, in conjunction with endogenously rearranged Ig heavy chains. Tg mice are also genetically deficient in endogenous kappa chains to permit tracking of the mLCV3 transgene. We show that mLCV3-Tg mice are susceptible to humoral autoimmunity against both collagen chains. Anti-alpha3(IV)NC1 collagen, but not anti-CII, mLCV3-encoded Ig are detected in serum of unmanipulated Tg mice, while Toll-like receptor ligands induce secretion of mLCV3-Tg autoantibodies of both collagen specificities from splenocytes ex vivo. This indicates developmental survival of mLCV3-Tg B cells reactive with each antigen, and is consistent with production of the two anti-collagen autoIg from distinct B cell populations. Reduced B cell numbers, low serum Ig kappa levels, low cell surface Ig kappa density, and abundant endogenous lambda chain expression suggest that subsets of IGKV3-encoded B cells are regulated in vivo by mechanisms that include deletion, anergy, and LC editing. These results support the notion that murine IGKV3 LCs contribute structural fitness to antigen binding sites that support diverse anti-collagen autoimmune responses, that these responses are regulated in vivo, and that these cells can nonetheless readily escape immune regulation.

Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models.

BACKGROUND: Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab origins or structure. This ignorance is due in part to the inability to recover monoclonal Ab by transformation of patients' blood cells. The aim of this study was to assess the suitability of two humanized models for this purpose. METHODS: NOD-scid-gamma immunodeficient mice were engrafted either with human CD34+ hematopoietic stem cells (HSC) (Hu-HSC mice) and immunized with alpha3(IV)NC1 collagen containing the Goodpasture epitopes or with nephritis patients' peripheral blood leukocytes (PBL) (Hu-PBL mice). After in vivo immune cell development and/or expansion, recovered human B cells were Epstein Barr virus (EBV)-transformed, screened for antigen (Ag) binding, electrofused with a mouse-human heterohybridoma, subcloned, and human Ab RNA sequenced by PCR after reverse transcription to cDNA. Flow cytometry was used to assess human B cell markers and differentiation in Hu-PBL mice. RESULTS: Sequence analysis of a human Ab derived from an immunized Hu-HSC mouse and reactive with alpha3(IV)NC1 collagen reveals that it is encoded by unmutated heavy and light chain genes. The heavy chain complementarity determining region 3, a major determinant of Ag binding, contains uncommon motifs, including an N-region somatically-introduced highly hydrophobic tetrapeptide and dual cysteines encoded by a uniquely human IGHD2-2 Ab gene segment that lacks a murine counterpart. Comparison of human and mouse autoantibodies suggests that structurally similar murine Ab may arise by convergent selection. In contrast to the Hu-HSC model, transformed human B cells are rarely recovered from Hu-PBL mice, in which human B cells terminally differentiate and lose expression of EBV receptor CD21, thus precluding their transformation and recovery. CONCLUSIONS: Hu-HSC mice reveal that potentially pathogenic B cells bearing unmutated Ig receptors reactive with the NC1 domain on alpha3(IV) collagen can be generated in, and not purged from, the human preimmune repertoire. Uniquely human gene elements are recruited to generate the antigen binding site in at least a subset of these autoantibodies, indicating that humanized models may provide insights inaccessible using conventional mouse models.