Selective organ specific inflammation in offspring harbouring microchimerism from strongly alloreactive mothers.

The origins of autoimmunity are not yet understood despite significant advances in immunology. The trafficking of maternal cells to the offspring represents the very first immunological event in foetal life and is reinforced during lactation. The persistence of maternal cells in offspring's tissues and circulation has been associated with several autoimmune disorders. However a direct causal effect has never been demonstrated. Maternal T cells specifically targeting foetal insulin producing cells have been shown to generate islet inflammation without directly participating in this process. Our objective was to evaluate if alloreactive maternal cells could directly trigger a graft-versus host like reaction or indirectly influence the development of the offspring's regulatory T cells favouring autoimmunity. We adopted a breeding strategy comparing genetically identical offspring from either strongly alloreactive transgenic mothers compared to immunodeficient mothers. We detected maternal alloreactive T cells in the offspring and early signs of inflammation in small intestine of 6 weeks old offspring. Interestingly, CD4(+) Foxp3(+) regulatory T cell frequency was diminished in mesenteric lymph nodes from eight months old offspring born of alloreactive mothers compared to offspring of immunodeficient mothers. Our study favours a hypothesis where highly alloreactive maternal cell microchimerism indirectly predisposes offspring to autoimmunity.

A review of upper urinary tract cytology performance before and after the implementation of The Paris System.

Urinary cytology (UC) is one of the primary diagnostic modalities used for the screening and surveillance of urothelial carcinoma. Despite its widespread use, UC has suffered from a lack of standardized or reproducible criteria and wide interobserver variability, particularly of the designation of atypical urothelial cells. The Paris System for Reporting Urinary Cytology (TPS), published in 2016, aimed to provide a standardized approach for evaluating UC by creating diagnostic categories with specific cytomorphologic criteria. Recent studies have primarily investigated the application of TPS on lower urinary tract specimens and have mostly shown that TPS implementation has improved the performance of UC specimens. Only a few studies have reported the impact of TPS on upper urinary tract (UUT) cytology. Additionally, there is uncertainty as to which cytological features are most predictive of high-grade urothelial carcinoma (HGUC) in the UUT. This review summarizes the literature regarding the utility and performance of UUT cytology and highlights findings before and after the implementation of TPS.

A review of urinary cytology in the setting of upper tract urothelial carcinoma.

Urothelial carcinomas of the upper urinary tract (UUT) are uncommon. Cytological examination of voided urine or washings from the UUT has been part of the standard workup for upper tract urothelial carcinoma (UTUC); however, its value remains controversial. The lack of uniform terminology and specific diagnostic criteria could also have contributed to the inferior performance of urinary cytology for detecting UTUC. The Paris System for Reporting Urinary Cytology (TPS) has provided a standardized reporting system for urinary cytology specimens with clearly defined cytomorphologic diagnostic criteria and found acceptance on an international level after its implementation in 2016. Recent studies have shown that TPS has led to improved diagnostic performance of urinary cytology; however, most of these studies had focused on the evaluation of lower urinary tract cytology specimens. Only a limited number of new research studies have analyzed the effect of TPS when applied to UUT cytology specimens. In the present report, we have summarized the current understanding and utility of UTUC, including its molecular biology, and reviewed the current literature.

Breast cancer metastasis to gynaecological organs: a clinico-pathological and molecular profiling study.

Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico-pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy-number profiling, and targeted sequencing of 386 cancer-related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0-20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0-18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A-like phenotype were over-represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co-expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A-like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression.

Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases.

Autoimmune enteropathy (AIE) is a rare disorder characterized by severe diarrhea and small intestinal mucosal atrophy resulting from immune-mediated injury. It remains a challenging diagnosis because of its clinicopathologic variability. To better understand its histopathologic features, we describe the gastrointestinal biopsy findings of 25 patients, including children and adults. The most common finding on small intestinal biopsy (13/25 cases, 52%) was villous blunting, expansion of the lamina propria by mixed but predominantly mononuclear inflammation, and neutrophilic cryptitis with or without crypt microabscesses. In 5 cases (20%), the duodenum exhibited changes indistinguishable from celiac disease, with villous blunting and intraepithelial lymphocytosis. Increased crypt apoptosis with minimal inflammation, resembling acute graft-versus-host disease, was observed in 4 cases (16%). The remaining 3 cases (12%) exhibited a mixture of 2 or more of the above patterns. Mucosal abnormalities outside the small intestine were present in all 24 cases with available biopsies (100%), with the stomach most commonly affected (19/22 cases, 86%), followed by the colon (14/22, 64%) and esophagus (5/18, 28%). Findings in non-small intestinal sites were variable and included mixed active and chronic inflammation, chronic inflammation alone, intraepithelial lymphocytosis, and increased apoptosis resembling acute graft-versus-host disease. In summary, AIE most commonly presents as an active enteritis with villous blunting and expansion of the lamina propria by mixed inflammation. Mucosal abnormalities are frequently seen elsewhere in the gut. AIE may thus be better regarded as a pan-gastrointestinal autoimmune disorder, and biopsies from sites other than the small intestine may greatly facilitate its diagnosis.