Significant outcomes associated with high-risk human papillomavirus negative Papanicolaou tests.

INTRODUCTION: The 2020 American Cancer Society guidelines preferred primary human papillomavirus (HPV) screening for cervical cancer prevention. Studies investigating the role of cytology in detection of cervical precancer/cancer have focused on high-grade squamous intraepithelial lesion (HSIL) or worse interpretations. Here, we have examined the significance of all those cytology results that require histologic follow-up as per the current management guidelines, regardless of the HPV test result. MATERIALS AND METHODS: A database search (September 2010 to December 2019) retrieved cervical Papanicolaou tests with any of the following interpretations: ≥ atypical squamous cells - cannot exclude HSIL or low-grade squamous intraepithelial lesion, HSIL cannot be excluded, and ≥ atypical glandular cells, not otherwise specified and its subcategories. Of these, those with concurrent negative HPV test result were included for further analysis. For this cohort, relevant clinical history and histologic follow-up (within 1 year) were recorded. RESULTS: The study cohort comprised 763 patients. Of them, 586 (76.8%) patients had histologic follow-up: 53 (9.0%) had ≥ HSIL/adenocarcinoma in situ; of which, 43 (81.1%) had prior abnormal cytology/histology/not otherwise specified history and/or HPV positivity, and 66 (11.3%) had HPV-unassociated neoplasia; of which, 60 (90.9%) had a known diagnosis or clinical signs/symptoms of the disease. CONCLUSION: With widespread adoption of risk-based approach to management, the role of cytology, by itself, will likely diminish in the detection of HPV-associated lesions. Additional data regarding the role of cytology in the screening of patients with no/unknown/limited history and in the detection/management of HPV-independent lesions may be helpful for designing future screening guidelines.

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.

A Niche for Plasma Cells: The Skin.

Antibodies are key components of the skin immune barrier, and antibodies directed toward skin structures can result in disease. Wilson et al. (2019) show that healthy skin is a niche for antibody secreting plasma cells and plasmablasts, and that inflammation and immunization increase their numbers. This work advances our understanding of skin associated B and plasma cells in health and disease.