IgG3 regulates tissue-like memory B cells in HIV-infected individuals.

Immunoglobulin G3 (IgG3) has an uncertain role in the response to infection with and vaccination against human immunodeficiency virus (HIV). Here we describe a regulatory role for IgG3 in dampening the immune system-activating effects of chronic HIV viremia on B cells. Secreted IgG3 was bound to IgM-expressing B cells in vivo in HIV-infected chronically viremic individuals but not in early-viremic or aviremic individuals. Tissue-like memory (TLM) B cells, a population expanded by persistent HIV viremia, bound large amounts of IgG3. IgG3 induced clustering of B cell antigen receptors (BCRs) on the IgM+ B cells, which was mediated by direct interactions between soluble IgG3 and membrane IgM of the BCR (IgM-BCR). The inhibitory IgG receptor CD32b (FcγRIIb), complement component C1q and inflammatory biomarker CRP contributed to the binding of secreted IgG3 onto IgM-expressing B cells of HIV-infected individuals. Notably, IgG3-bound TLM B cells were refractory to IgM-BCR stimulation, thus demonstrating that IgG3 can regulate B cells during chronic activation of the immune system.

Masculinizing chest wall gender-affirming surgery: Clinical outcomes of 73 subcutaneous mastectomies using the double-incision and semicircular incision techniques.

Masculinizing chest wall gender-affirming surgery is an important element in the treatment of gender dysphoria. In this study, we report an institutional series of subcutaneous mastectomies and aim to identify the risk factors for major complications and revision surgery. A retrospective review of consecutive patients who underwent primary masculinizing top surgery via subcutaneous mastectomy at our institution through July 2021 was performed. Demographics and clinical characteristics were recorded as well as major complications and revision surgeries. Time-to-event analyses were performed to assess predictors of major complications and revision surgery. Seventy-three consecutive patients (146 breasts) were included. The mean age and the mean body mass index were 25.2 ± 7 years and 27.6 ± 6.5 kg/m2, respectively. The mean follow-up time was 7.9 ± 7.5 months. None of the patients had a history of chest wall radiation or breast surgery. Double incision with free nipple grafting was the most common technique (n = 130, 89%), followed by periareolar semicircular incision (n = 16, 11%). The mean resection weight was 524.7 ± 377.7 g. Concomitant suction-assisted lipectomy was performed in 48 (32.9%) cases. The rate of major complications was 2.7%. Revision surgery was performed in 8 (5.4%) cases. Concomitant liposuction was significantly associated with a lower rate of revision surgery (p = 0.026). Masculinizing chest wall gender-affirming surgery is a safe procedure with a low rate of revision. Concomitant liposuction significantly reduced the need of revision surgery. Future studies utilizing patient-reported outcomes are still required to better assess the success of this procedure.

Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation.

Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet-expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome. Confocal microscopy and quantitative imaging revealed that T-bethi B cells in LN of HIV-infected chronically viremic individuals distinctly accumulated outside germinal centers (GC), which are critical for optimal antibody responses. In single-cell analyses, LN T-bethi B cells of HIV-infected individuals were almost exclusively found among CD19hi MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19hiT-bethi MBC and displayed a distinct transcriptome, with features similar to CD19hiT-bethi MBC in blood and LN GC B cells (GCBC). LN CD19hiT-bethi MBC were also related to GCBC by B cell receptor (BCR)-based phylogenetic linkage but had lower BCR mutation frequencies and reduced HIV-neutralizing capacity, consistent with diminished participation in GC-mediated affinity selection. Thus, in the setting of chronic immune activation associated with HIV viremia, failure of HIV-specific B cells to enter or remain in GC may help explain the rarity of high-affinity protective antibodies.