Glucocorticoid-responsive lymphocytic parathyroiditis and hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor: a case report and literature review.

OBJECTIVE: Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with autoantibodies against the calcium-sensing receptor (anti-CaSR) are rare and poorly understood conditions. Here, we describe a patient with acquired parathyroid hormone (PTH)-dependent hypercalcemia with associated hypocalciuria, found to have true lymphocytic parathyroiditis on histopathology, and circulating anti-CaSR antibodies in serum. DESIGN AND METHODS: A 64-year-old woman was referred to our clinic for persistent hypercalcemia after a subtotal parathyroidectomy. She was normocalcemic until the age of 63 years when she was diagnosed with primary hyperparathyroidism. She underwent subtotal parathyroidectomy with appropriate intraoperative PTH decline. Two weeks post-parathyroidectomy, she presented with persistent hypercalcemia and hyperparathyroidism. Urine studies revealed an inappropriately low 24-h urine calcium (Ca)/creatinine clearance ratio. Surgical pathology was consistent with true lymphocytic parathyroiditis with lymphoid follicles. The presence of circulating anti-CaSR antibodies was detected by immunoprecipitation of CaSR by the patient's serum. After a 4-week course of prednisone, serum Ca and PTH normalized, and her anti-CaSR titers declined. She remains normocalcemic 10 months after the discontinuation of glucocorticoid therapy. We present this patient in the context of the relevant published literature on lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia related to anti-CaSR antibodies. CONCLUSIONS: Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with anti-CaSR antibodies is a very rare yet important condition to be considered in a patient with acquired PTH-dependent hypercalcemia with inappropriate hypocalciuria. Although subtotal parathyroidectomy is unlikely to correct the hypercalcemia, this entity may respond to a short course of prednisone therapy.

Glatiramer acetate (GA) therapy induces a focused, oligoclonal CD8+ T-cell repertoire in multiple sclerosis.

We have demonstrated that GA therapy induces a differential upregulation of GA-specific, cytotoxic/suppressor CD8+ T-cell responses in MS patients. We utilized a novel combination of flow sorting and anchored PCR to analyze the evolving clonal composition of GA-specific CD4+ and CD8+ T-cells. TCRbeta chain analysis revealed the development of an oligoclonal GA-specific CD8+ repertoire with persistence of dominant clones over long periods. Interestingly, some sequences resembled published oligoclonal CD8+ TCR sequences from MS lesions. In contrast, GA-specific CD4+ responses were polyclonal and showed continual evolution of their repertoire. This clonotypic and functional analysis provides mechanistic insights into GA therapy.

Solid pseudopapillary neoplasm collides with a well-differentiated pancreatic endocrine neoplasm in an adult man: case report and review of histogenesis.

OBJECTIVES: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, clinicopathologically distinct neoplasm with a tendency to affect young women. The histogenesis of SPN is not well defined. Pancreatic endocrine neoplasms (PENs) are also uncommon tumors of the pancreas. METHODS: Our comprehensive review of the literature did not yield any reported cases of collision tumors of the above two neoplasms. We report a case of such a collision tumor in a 45-year-old man. RESULTS: This tumor was an incidental finding on computed tomography, followed by fine-needle aspiration confirmation of a tumor that was initially diagnosed as an SPN only. A histologic examination of a 2.1-cm mass following distal pancreatectomy revealed a 0.7-cm PEN partly engulfed by an SPN. The tumors showed different morphologic and immunohistochemical features, confirming the presence of a collision tumor. CONCLUSIONS: A comparative analysis of immunoprofiles of these tumors yielded interesting findings, enabling us to postulate that SPNs may originate from a multipotential primordial cell that may follow different differentiation pathways, such as endocrine, epithelial, and acinar. The ultrastructures and immunophenotypic characteristics appear to support this hypothesis.

Clonal composition of neuroantigen-specific CD8+ and CD4+ T-cells in multiple sclerosis.

Patients with multiple sclerosis (MS) show a high prevalence of myelin-reactive CD8+ and CD4+ T-cell responses, which are the putative effectors/modulators of CNS neuropathology. Utilizing a novel combination of short-term culture, CFSE-based sorting and anchored PCR, we evaluated clonal compositions of neuroantigen-targeting T-cells from RRMS patients and controls. CDR3 region analysis of TCRß chains revealed biased use of specific TCRBV-bearing CD4+ clones. CD8+ clones showed homology to published TCR from CNS-infiltrating T-cells in MS lesions. These studies are the first description of TCR usage of CNS-specific CD8+ T-cells and provide insights into their potential regulatory role in disease.

High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) with features suggestive of T-cell-mediated pathology. Most prior reports have focused on CD4(+) T cells with the underlying assumption that MS is predominantly a CD4(+) T helper 1 (Th1)-mediated disease. In this report, we used a novel flow cytometric approach to evaluate autoreactive T-cell responses against a large variety of neuroantigenic targets. We found that both CD4(+) and CD8(+) T cells targeted against several CNS autoantigens were widely prevalent in patients with MS and healthy individuals. Whereas the distribution of CD4(+) responses was similar in different groups, patients with relapsing-remitting MS showed a higher proportion of CNS-specific CD8(+) responses. Autoreactive CD4(+) T cells from patients with MS exhibited a more differentiated Th1 phenotype compared with healthy subjects. Similarly, CNS-specific CD8(+) T-cell responses from patients with MS were functionally distinct from those in healthy individuals. Collectively, these studies reveal the high prevalence of class I-restricted autoreactive CD8(+) T-cell responses in MS that has been underappreciated thus far. The results emphasize the need to evaluate both CD4(+) and CD8(+) T-cell responses in MS and to make both subsets a consideration in the development of novel therapeutic strategies.