STIM1 is essential for Fcgamma receptor activation and autoimmune inflammation

Fcgamma receptors (FcgammaRs) on mononuclear phagocytes trigger autoantibody and immune complex-induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRgamma-based activation is critical in the pathogenesis of these diseases, although the contribution of FcgammaR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum-resident calcium sensor, STIM1, cannot activate FcgammaR-induced Ca(2+) entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcgammaR activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunologic diseases.     

CD166 Expression, Characterization, and Localization in Salivary Epithelium: Implications for Function During Sialoadenitis

CD166 is an Ig superfamily molecule that binds homotypically to itself and heterotypically to CD6. Interactions between CD6 and CD166 are important during immune development and in alloreactivity. CD166 is expressed at increased levels in selected cancers and in rheumatoid arthritis synovium. Knowledge that CD166 was expressed in normal human salivary epithelium led to these studies of CD166 and CD6 in diseased mouse salivary glands, that resemble pathology seen in the human disease, Sjögren's syndrome. We showed that in mouse salivary epithelium CD166 was expressed but that expression of CD166 did not necessarily predict its function. Recombinant soluble CD6-Ig bound to CD6 ligands (CD6L) on transformed and freshly isolated salivary epithelial cells. Cross-blocking studies showed that binding of CD6-Ig to salivary epithelium was in part dependent on CD166, but that CD6-Ig binding may also involve additional CD6L. Binding of CD6-Ig was sensitive to trypsin digestion but resistant to digestion by collagenase and sialidase. Anti-CD166 ab precipitated CD166 from salivary epithelium pre- and post-treatment with the pro-inflammatory cytokine IFN-γ. In contrast CD6-Ig only precipitated CD166 from IFN-γ treated cells. More extensive colocalization between CD166 and the actin cytoskeleton was observed in sialoadenitis epithelium compared to control. We conclude that during sialoadenitis, CD166 undergoes a gain of function, resulting in closer association with the actin cytoskeleton and increased capacity to bind CD6. We suggest that altered CD166 function may contribute to the pro-inflammatory milieu during sialoadenitis seen in Sjögren's syndrome.     

Report of an angiosarcoma mimic: cutaneous aneurysmal fibrous histiocytoma

Aneurysmal fibrous histiocytoma is an unusual variant of the spectrum of fibrous histiocytomas with the peculiar morphologic appearance of a benign aneurysmal vasoformative process that ultimately culminates in multiple microhemorrhages within the tumor. It looks strikingly different from the usual cutaneous lesions encountered in clinical dermatology practice. A single report of a cutaneous aneurysmal fibrous histiocytoma in the skin of the back of a 60-year-old male is described with emphasis on the immunostaining pattern and review of the literature. There is a significant potential for confusion of this lesion with other cutaneous lesions, clinically as well as pathologically. In our case, the patient presented with a lesion that clinically resembled a hemangioma, was pathologically interpreted initially to be an angiosarcoma, and finally, the revised pathology was interpreted as an aneurysmal variant of a fibrous histiocytoma. Caution is warranted to avoid misinterpretation of cutaneous fibrohistiocytic tumors.     

Minimal metastatic disease in sentinel lymph nodes in breast carcinoma: some modest proposals to refine criteria for "isolated tumor cells"

Axillary lymph node status is one of the most important prognostic factors in breast carcinoma. The weight of cumulative evidence suggests that the development of the sentinel lymph node (SLN) biopsy procedure has not only allowed for accurate lymph node-staging but has also helped avoid the morbidity of a full axillary dissection in those patients who are unlikely to have metastatic tumor in that location. The detection of metastases in SLNs is facilitated by the, now relatively routine, enhanced histopathologic examination via step-sectioning and immunohistochemistry. In clinical terms, the finding of a metastatic deposit that measures between 0.2 and 2 mm, that is, "micrometastasis" in a SLN is largely noncontroversial; however, the presence of smaller metastatic foci detected either by routine hematoxylin and eosin stain or by cytokeratin immunostain [<0.2 mm, ie, so-called "isolated tumor cells (ITCs)"] has remained problematic since the advent of the SLN biopsy. In this communication, attention is drawn to the broad morphologic range of metastatic disease in SLN that may be placed in the category of so-called ITC. To facilitate the reproducible classification of the various strata of minimal metastasis in sentinel lymph nodes, we recommend the following: (1) the term "isolated tumor cell" (note singular form) be restricted to cases that show the presence of only a single tumor cell. (2) In situations where there are multiple isolated single cells and/or cell cluster(s) present and each cluster measures<0.2 mm, the term "submicroscopic metastasis" be adopted and an actual count of tumor cells present may be given. (3) Restrict the use of the term micrometastasis to cases wherein the largest metastatic focus is larger than 0.2 mm but smaller than 2.0 mm.     

Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice

Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody-induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcgammaRI and FcgammaRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcgammaR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a--produced by and acting on FcgammaR--and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.     

Thirty-one years of clinical experience with "nuclear-powered" pacemakers

From 1973 through 1987, 164 radioisotope powered ("nuclear") pacemakers were implanted in 139 patients at the Newark Beth Israel Medical Center. Patient survival was much as might be expected from an age group as selected for this program. At 31 years (January 2005), 12 of the 139 patients (9%) were still alive. The experience reported here encompassed a span of 16 years of implantation with a follow-up of slightly more than 31 years. The problems encountered along the way were not remarkably different from those encountered in general clinical experience with pacemakers, except that the number of reoperations was fewer. In fact, most patients died with the initial implant in place. Deaths most commonly were due to cardiac causes (54%). The frequency of malignancies was similar to that of the age-matched population; primary tumor sites were randomly distributed. These results show that nuclear pacemakers were safe and reliable. Their longevity and the resulting decrease in reoperations offset their greater initial cost.