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Sperm antigens egress mouse testes: Protection by Treg-dependent system tolerance [Meeting Abstract]

Tung, K; Harakal, J; Qiao, H; Rival, C; Paul, L; Hardy, D; Cheng, Y C; Schegg, K; Yan, W; Goldberg, E
Problem: FOXP3+ regulatory T cells (Treg) are crucial for prevention of organ-specific autoimmune disease. To maintain their regulatory capacity, the peripheral Treg requires continuous recognition of the cognate tissue antigens (Ag). The Meiotic sperm Ag are hidden by BTB and therefore may not be able to interact with the Treg. Cancer-testis Ag expressed in human testes should likewise be highly immunogenic as cancer vaccine Ag. However, these are assumptions not supported by experimental evidence. Herein, we address the physiological relevance of Treg-dependent tolerance for the different unique autoantigens in normal testis. XXMethods and Results: To investigate Treg as tolerance mechanism, we deplete them from DEREG mice that express FOXP3-Diphtheria toxin receptors. Treg-depleted male mice spontaneously produce antibody (Ab) to Leydig cells, including steroid enzymes 450 scc and 17a-hydroxylase; and to spermatogonia. Documenting the tolerance status of these interstitial Ag is clinically relevant because Treg-deficient autoimmune polyendocrine syndrome patients produce Ab to the Leydig cell Ag, and spermatogonial Ag are cancer vaccine candidates. Next, we discover the sperm Ag lactate dehydrogenase 3 (LDH3), but not zonahesin, continuously exits the seminiferous tubules of normal mice: LDH3 forms immune complexes outside the BTB with serum Ab. The 'exposed' sperm antigens are contents of the residual bodies and the cytoplasmic droplets, derived from spermatids discarded at spermiation. Sertoli cells destroy most residual bodies, but the intact ones can reach interstitial space. Importantly, Treg-depleted DEREG mice develop autoimmune orchitis, produce Ab to LDH3 but not zonadhesin. In contrast, vasectomized mice with Treg depletion produce Ab to zonadhesin but not LDH3. Finally, to generalize the above findings, vasectomized mice with Treg depletion produce Ab to the 'hidden' acrosome Ag and not the cytoplasmic droplets, whereas Treg-depleted DEREG mice produce Ab against cytoplasmic droplets but not sperm acrosome. XXConclusion(s): We conclude that the complete testis antigen sequestration concept is invalid. Some testis and sperm Ag are normally exposed and they are protected by the Treg. Similarly, the exposed cancer/testis Ag, protected by the Treg, may not be uniquely immunogenic. Our results support a new paradigm for research on testis/ sperm autoimmunity and cancer/testis vaccine development
ISSN: 1600-0897
CID: 4913472

Incidental thyroid carcinoma in graves'disease-should we be concerned? [Meeting Abstract]

Ho, E; Cheng, Y; Liu, C; Sum, M; Ogilvie, J; Givi, B; Patel, K
The incidence of thyroid cancer in Graves'Disease (GD) patients is estimated to be low. However, it is unclear what impact the recent rise in the incidence of thyroid cancers has had in this population. Furthermore, it is not clear if these cancers behave more aggressively than cancers in the general population. We investigated the incidence of malignancy and its features in a contemporary cohort of GD patients treated by surgery. All patients who underwent thyroidectomy for GD in our center were reviewed from 2013-2018. Demographics, clinicopathologic features, rate of incidental cancer and outcomes were reviewed. We identified 130 patients with GD who underwent thyroidectomy. Median age was 40.5 (16-80). Majority were female (112, 86%). All but five (4%) were radioactive iodine naive. Thirtyfour (26%) were found to harbor malignancy. While the majority (18, 53%) were papillary microcarcinoma; 12 (34%) had multifocal disease; 10 (29%) had tall cell features, 3 (9%) had positive lymph nodes, and 2 (6%) had extrathyroidal extension. One patient (3%) was diagnosed with follicular carcinoma. No permanent hyperparathyroidism or recurrent laryngeal nerve injury was encountered. With a median follow up of 23 months no recurrences were identified. The risk of incidental malignancy in GD patients was high in our cohort. While the majority were low risk microcarcinomas, a number of patients harbored higher risk tall cell features. Our data suggest that for GD patients who are medically managed, careful surveillance and biopsy of suspicious nodules might be warranted. The outcome of surgical treatment was excellent for controlling both hyperthyroidism and cancer
ISSN: 1557-9077
CID: 4187912

Chinese herbal medicine for miscarriage affects decidual micro-environment and fetal growth

Piao, L; Chen, C-P; Yeh, C-C; Basar, M; Masch, R; Cheng, Y C; Lockwood, C J; Schatz, F; Huang, S J
INTRODUCTION: Intrauterine growth restriction complicates 5-10% of pregnancies. This study aims to test the hypothesis that Chinese herbal formula, JLFC01, affects pregnancy and fetal development by modulating the pro-inflammatory decidual micro-environment. METHODS: Human decidua from gestational age-matched elective terminations or incomplete/missed abortion was immunostained using anti-CD68 + anti-CD86 or anti-CD163 antibodies. qRT-PCR and Luminex assay measured the effects of JLFC01 on IL-1beta- or TNF-alpha-induced cytokine expression in first trimester decidual cells and on an established spontaneous abortion/intrauterine growth restriction (SA/IUGR)-prone mouse placentae. The effect of JLFC01 on human endometrial endothelial cell angiogenesis was evaluated by average area, length and numbers of branching points of tube formation. Food intake, litter size, fetal weight, placental weight and resorption rate were recorded in SA/IUGR-prone mouse treated with JLFC01. qRT-PCR, Western blot and immunohistochemistry assessed the expression of mouse placental IGF-I and IGF-IR. RESULTS: In spontaneous abortion, numbers of decidual macrophages expressing CD86 and CD163 are increased and decreased, respectively. JLFC01 reduces IL-1beta- or TNF-alpha-induced GM-CSF, M-CSF, C-C motif ligand 2 (CCL2), interferon-gamma-inducible protein-10 (IP-10), CCL5 and IL-8 production in first trimester decidual cells. JLFC01 suppresses the activity of IL-1beta- or TNF-alpha-treated first trimester decidual cells in enhancing macrophage-inhibited angiogenesis. In SA/IUGR-prone mice, JLFC01 increases maternal food intake, litter size, fetal and placental weight, and reduces fetal resorption rate. JLFC01 induces IGF-I and IGF-IR expression and inhibits M-CSF, CCL2, CCL5, CCL11, CCL3 and G-CSF expression in the placentae. DISCUSSION: JLFC01 improves gestation by inhibiting decidual inflammation, enhancing angiogenesis and promoting fetal growth.
PMID: 25771406
ISSN: 1532-3102
CID: 2729272