Hirsch Demant (porchoutput4)

Mutations in the DNA-binding domain (DBD), exemplified by T385M, frequently correlate with the development of autoimmunity in about one-third of affected individuals, occasionally associated with an increase in T-helper 1 (Th1) and T-follicular helper (Tfh) CD4 effector T cells, displaying a similar pattern to cells activated by infection-induced STAT1 signaling. Nevertheless, the environmental and molecular underpinnings of autoimmunity in STAT1 gain-of-function cases are not yet understood. Using specific-pathogen-free (SPF) conditions, we developed Stat1T385M/+ mutant mice to exemplify the immune consequences of STAT1 DBD gain-of-function. Stat1T385M/+ lymphocytes possessed greater baseline Stat1 levels and exhibited elevated IFNg-stimulated pStat1. Young mutants displayed an augmentation in Tfh-like cells, but older mutants experienced the onset of autoimmunity, accompanied by an increase in Tfh-like cells, B-cell activation, and the formation of germinal centers. Mutant female organisms displayed these immune alterations at an earlier stage and with greater intensity than their male counterparts, indicating a substantial sex-based effect of Stat1T385M-induced immune dysregulation. Analysis of single-cell RNA sequencing (scRNA-Seq) data showed Stat1T385M driving the transcription of gene programs connected to germinal centers within both B and T lymphocytes. In contrast, T cells experienced the most profound transcriptional impact, leading to a deviation from normal CD4 T-cell activation and promoting both Tfh-like and Th1-like effector programs. The combined data show that, when no clear infection is present, the Stat1T385M mutation negatively impacts the stable state of naive CD4 T cells, triggering increased numbers and maturation of atypical Tfh/Th1-like helper and GC-like B cells. This cascade of events culminates in sex-specific autoimmune responses, implying a model for STAT1 gain-of-function-induced immune system disruption and subsequent autoimmune conditions in humans. An analysis of the data reveals that in the absence of detectable infection, the Stat1T385M variant disrupts the normal function of naive CD4 T cells, leading to their proliferation and development into atypical T follicular helper/Th1-like and germinal center-like B cells. This process culminates in sex-specific autoimmune responses, offering a possible model for STAT1 gain-of-function-induced immune system dysfunction and autoimmune disorders in humans. Exocytosis, a precisely regulated cellular process, is fundamental to the exchange of information between cells. The pivotal role of this element extends beyond neurotransmission and hormone release, encompassing its crucial contribution to the immune system's cytokine and cytotoxic molecule discharge. Immunological synapse formation in cytotoxic T lymphocytes (CTLs) is essential for the delivery of cytotoxic substances, such as granzymes and perforin, which are contained in lytic granules and expelled by exocytosis. A complete picture of the molecular events leading to their fusion with the plasma membrane is still incomplete. The molecular players driving the regulated exocytosis of cytotoxic T lymphocytes are discussed in this review, emphasizing their parallels and divergences with the process of neuronal synaptic transmission. In addition, we explore the strengths and limitations of both systems with a view to examining exocytosis. Currently, the diagnosis of latent tuberculosis infection (LTBI) is accomplished through the assessment of interferon-gamma (IFN-) secretion in response to stimulation. The presence of MTB antigens signals infection, their absence signifies no infection. Prolonged and consistent contact with Mtb may not lead to infection in some individuals, who are referred to as resisters. Our investigation explored whether cytokines, chemokines, and antibodies are correlated with the ability to resist infection by Mtb. Our hypothe