Roles of Bone Morphogenetic Protein Receptor 1A in Germinal Centers and Long-Lived Humoral Immunity.

In response to T-dependent Ag, germinal centers (GC) generate bone marrow-resident plasma cells (BMPC) and memory B cells (MBC). In this study, we demonstrate that the bone morphogenetic protein receptor 1A (BMPR1A) signaling pathway, which regulates differentiation and self-renewal in multiple stem cell populations, regulates GC dynamics and resultant establishment of BMPC and MBC. Expression studies using quantitative PCR and novel Bmpr1aIRES.EGFP reporter mice demonstrated that Bmpr1a expression is upregulated among GC B cells (GCBC) and subsets of MBC, bone marrow plasmablasts, and BMPC. In immunized mice carrying B cell-targeted Bmpr1a gene deletions, the GC response was initially diminished. Subsequently, the GCBC compartment recovered in size, concurrent with accumulation of GCBC that carried unmodified rather than deleted Bmpr1a alleles. Similarly, the resulting class-switched MBC and BMPC carried retained non-recombined alleles. Despite the strong selective pressure for "leaky" B cells that retained Bmpr1a, there was a permanent marked reduction in switched bone marrow Ab-forming cells (plasmablasts + plasma cells), BMPC, MBC, and Ag-specific serum IgM in mice carrying B cell-targeted Bmpr1a gene deletions. These findings demonstrate a novel role for BMPR1A in the modulation of the B cell response and in the establishment of long-term memory.

Factors affecting patient presentation at a national dermatology referral clinic in Kampala, Uganda.

BACKGROUND: This study sought to gain a better understanding of the patient population in Kampala and was further designed to elucidate barriers that may delay individuals from receiving proper dermatologic care. METHODS: The study took place at the dermatovenereology clinic of a tertiary care hospital in Kampala. New adult patients were surveyed in July and August of 2013. The primary dependent variable was time from reported onset of symptoms to presentation to the clinic. Participant demographic characteristics, medical and treatment history, and perception of illness as measured by the dermatology life quality index (DLQI) were assessed. RESULTS: A total of 232 subjects participated in the study. The most common skin diseases were allergic (20.3%), infectious (15.1%), follicular (7.8%), and papulosquamous (7.8%) disorders. Greater home distance from the clinic correlated with later presentation times (r = 0.259, P < 0.001). DLQI score was not correlated with presentation time. HIV+ individuals presented earlier (mean 5 vs. 11 months, P = 0.043) and had higher DLQI scores (mean 12.6 vs. 9.3, P = 0.006) than HIV- individuals. The majority of participants (72.5%) had contact with at least one other healthcare worker (HCW) for management of their dermatologic symptoms; 65.8% reported that these previous treatments were ineffective. CONCLUSIONS: Efforts to educate HCWs should be focused on districts outside of Kampala and highlight recognition and proper treatment of allergic diseases. HCWs should aggressively treat skin problems in HIV+ individuals. HCWs practicing in Kampala without formal dermatological training should refer patients with skin disease to the clinic, as patients may receive care that is more appropriate.

Paired comparison of the sensitivity and specificity of multispectral digital skin lesion analysis and reflectance confocal microscopy in the detection of melanoma in vivo: A cross-sectional study.

BACKGROUND: Several technologies have been developed to aid dermatologists in the detection of melanoma in vivo including dermoscopy, multispectral digital skin lesion analysis (MDSLA), and reflectance confocal microscopy (RCM). To our knowledge, there have been no studies directly comparing MDSLA and RCM. OBJECTIVE: We conducted a repeated measures analysis comparing the sensitivity and specificity of MDSLA and RCM in the detection of melanoma (n = 55 lesions from 36 patients). METHODS: Study patients (n = 36) with atypical-appearing pigmented lesions (n = 55) underwent imaging by both RCM and MDSLA. Lesions were biopsied and analyzed by histopathology. RESULTS: RCM exhibited superior test metrics (P = .001, McNemar test) compared with MDSLA. Respectively, sensitivity measures were 85.7% and 71.4%, and specificity rates were 66.7% and 25.0%. LIMITATIONS: The sample size was relatively small and was collected from only one dermatologist's patient base; there was some degree of dermatopathologist interobserver variability; and only one confocalist performed the RCM image evaluations. CONCLUSION: RCM is a useful adjunct during clinical assessment of in vivo lesions suspicious for melanoma or those requiring re-excision because of high level of dysplasia or having features consistent with an atypical melanocytic nevus with severe cytologic atypia.

Phototherapy: Kids are not just little people.

Phototherapy is the delivery of treatments in the form of visible or ultraviolet light for the therapeutic care of a patient. Usage of phototherapy in children is affected by limited data in the medical literature, the inability of some children to stand still during the delivery of therapy, parental concerns regarding risks of therapy, and scheduling difficulties. Despite the limitation of data, there are publications in support of usage of phototherapy, especially for psoriasis, atopic dermatitis, and vitiligo in both children and adults. This contribution provides an overview of the utility of phototherapy in skin conditions with a specific focus on the differences that exist in the data on and the delivery of phototherapy for adults and children.

CD73 expression is dynamically regulated in the germinal center and bone marrow plasma cells are diminished in its absence.

CD73 catalyzes the conversion of extracellular nucleosides to adenosine, modulating inflammatory and T cell responses. Elevated expression of CD73 marks subpopulations of murine memory B cells (MBC), but its role in memory development or function is unknown. Here, we demonstrate that CD73 is progressively upregulated on germinal center (GC) B cells following immunization, is expressed at even higher levels among T follicular helper cells, but is absent among plasma cells (PC) and plasmablasts (PB). We analyzed the T-dependent B cell response in CD73 knockout mice (CD73KO). During the early response, CD73KO and wild type (WT) mice formed GCs, MBCs and splenic PBs and PCs similarly, and MBCs functioned similarly in the early secondary response. Late in the primary response, however, bone marrow (BM) PCs were markedly decreased in CD73KO animals. Tracking this phenotype, we found that CD73 expression was required on BM-derived cells for optimal BM PC responses. However, deletion of CD73 from either B or T lymphocytes alone did not recapitulate the phenotype. This suggests that CD73 expression is sufficient on either cell type, consistent with its function as an ectoenzyme. Together, these findings suggest that CD73-dependent adenosine signaling is prominent in the mature GC and required for establishment of the long-lived PC compartment, thus identifying a novel role for CD73 in humoral immunity.

CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation.

Germinal center (GC) B cells and T follicular helper (T(FH)) cells interact in the production of high-affinity long-lived plasma cells (PCs) and memory B cells, although the mechanisms regulating the formation of these long-lived populations remain unclear. Because CD80 is one of the few markers shared by human and murine memory B cells, we investigated its role in the development of GCs, memory cells, and PCs. In CD80-deficient mice, fewer long-lived PCs were generated upon immunization compared with that in B6 controls. In concert, the absence of CD80 resulted in an increase in apoptotic GC B cells during the contraction phase of the GC. CD80(-/-) mice had fewer T(FH) cells compared with that of B6, and residual T(FH) cells failed to mature, with decreased ICOS and PD-1 expression and decreased synthesis of IL-21 mRNA. Mixed bone marrow chimeras demonstrated a B cell-intrinsic requirement for CD80 expression for normal T(FH) cell and PC development. Therefore, B cell expression of CD80 plays a critical role in regulating B-T interactions in both early and late GC responses. This, in turn, results in impaired ability to produce long-lived PCs. These data provide new insights into the development of GCs and Ab-forming cells and the functions of CD80 in humoral immunity.