Biology subjects

Kashkar, H.

Publications and source records attributed to Kashkar, H..

4 recordsLinked to original sources

bioRxiv2026

Fitness and immune-escape within germinal centers shape premalignant evolution toward lymphoma

Germinal centers (GCs) support physiological B-cell mutagenesis and are considered lymphoma-permissive; nevertheless, lymphoma development is uncommon. Human in situ follicular neoplasia (ISFN) captures this paradox: premalignant B-cells can persist within GCs for prolonged periods without progressing to overt lymphoma. We found that human ISFN, but not normal GCs, are infiltrated by CD8 T-cells, suggesting that premalignant GC B-cells are locally immune-surveilled. Using mouse models that separate early premalignant fitness from lymphoma-associated evolution, we show that fitness-enhanced premalignant GC B-cells expand transiently but are selectively eliminated by infiltrating cytotoxic CD8 T-cells, while normal GC B-cells are spared. By contrast, evolved premalignant GC B-cells retain their fitness but disable productive CD8 T-cell cytotoxic differentiation, allowing persistence and lymphoma-like transcriptional and genomic evolution. These findings establish GCs as active immune-surveillance sites and show that progression from premalignancy to lymphoma requires both enhanced GC fitness and escape from local immune control. Key findingsGCs undergo active immune-surveillance to detect premalignant B-cells. Premalignant GC B-cells trigger cytotoxic CD8 T-cell responses. Lymphoma-associated evolution enables immune-escape within GCs. Fitness and immune-escape drive evolution from premalignancy to lymphoma. BlurbGerminal centers are considered lymphoma-permissive; however, progression from premalignancy is uncommon. Using models of human in situ follicular neoplasia, Zhang et al. demonstrate that infiltrating CD8 T-cells actively eliminate premalignant GC B-cells. Co-occurrence of lymphoma-like alterations blocks this cytotoxic T-cell response, driving immune escape and lymphoma evolution.

cancer biology↗

bioRxiv2026

Distributed Clonal Deletion Prevents Autoimmune Disease Progression

Self-reactive B cells are generated during normal development and can acquire increased pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification following activation. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that clonal deletion is enforced through temporally distinct mitochondrial apoptosis (MOMP) checkpoints that differentially regulate autoreactive B cell fate and disease progression. Using conditional Bcl-2 expression to inhibit MOMP either before or after B cell activation, we find that early inhibition permits the survival and maturation of autoreactive B cells after peripheral egress, expanding the pool of cells available for activation. These cells subsequently undergo AID-dependent diversification, producing class-switched IgG autoantibodies with expanded antigen breadth that target a wider range of self-antigens and drive lethal, female-biased autoimmune disease characterized by complement activation and kidney pathology. In contrast, inhibition of MOMP only after activation allows the accumulation of germinal center, switched memory, and plasma cells and promotes autoantibody production, but results in more restricted IgG autoreactivity, limited complement activation and limited tissue damage, and normal survival. Notably, early MOMP inhibition does not expand immature bone marrow B cells, indicating that a major clonal deletion checkpoint operates in the periphery rather than during initial B cell generation. Together, these findings support a Distributed Clonal Deletion Model in which early checkpoints restrict the entry of autoreactive B cells into diversification pathways, while later checkpoints limit the persistence of diversified autoreactive clones, thereby constraining autoimmune disease progression. One Sentence SummaryDistributed clonal deletion prevents autoimmune disease progression by restricting the breadth of autoreactive clones entering immune responses, with early MOMP checkpoints limiting diversification and later checkpoints constraining persistence.

immunology↗

bioRxiv2026

Modes of programmed macrophage cell death govern outcome of cutaneous wound healing

Misregulation of tissue repair programs can severely compromise repair outcome. Timely clearance of inflammatory macrophages through regulated cell death is a prerequisite for resolution of inflammation and successful repair. How different modes of macrophage regulated cell death regulate repair and direct healing outcome remains unclear. Using inducible genetic models to trigger macrophage necroptosis (FADDiMKO) or enhance apoptosis of macrophages (cIAP1iMKOcIAP2-/-), we reveal opposing effects on the architecture of the wound tissue. Macrophage necroptosis profoundly disrupted tissue organization: FADDiMKO wounds exhibited reduced numbers of reparative (IL-4RLy6Clow) macrophages, delayed inflammatory resolution, accompanied by a hemorrhagic granulation tissue and reduced myofibroblast differentiation in the mid-phase of repair. In striking contrast, increased apoptosis preserved fundamental tissue architecture and vascular integrity, and reduced scar formation. Furthermore, single-cell transcriptomics demonstrated that macrophage necroptosis disrupts tissue-wide cellular communication networks essential for coordinated repair, in particular macrophage-fibroblast crosstalk. These findings establish that wound healing quality depends on both mode and rate of macrophage programmed death, providing a framework for therapeutic targeting of macrophages in wound healing disorders and fibrotic diseases.

immunology↗

bioRxiv2023

FADD- and RIPK3-mediated cell death ensures timely clearance of wound macrophages and promotes wound healing

Cells of the monocyte/macrophage lineage are an integral component of the bodys innate ability to restore tissue function after injury. In parallel to mounting an inflammatory response, clearance of monocytes/macrophages from the wound site is critical to re-establish tissue functionality and integrity during the course of healing. The role of regulated cell death in macrophage clearance from damaged tissue and its implications for the outcome of the healing response is little understood. Here, we explored the role of macrophage-specific FADD-mediated cell death on Ripk3-/- background in a mechanical skin injury model in mice. We found that combined inhibition of RIPK3-mediated necroptosis and FADD-caspase-8-mediated apoptosis in macrophages profoundly delayed wound healing. Importantly, RIPK3 deficiency alone did not considerably alter the wound healing process and macrophage population dynamics, arguing that inhibition of FADD-caspase-8-dependent death of macrophages is primarily responsible for the delayed wound closure. Notably, TNF blockade reversed the accumulation of Ly6Chigh macrophages induced by combined deficiency of FADD and RIPK3, indicating a critical dual role of TNF-mediated pro-survival and cell death signalling, particularly in this highly pro-inflammatory macrophage subset. Our findings reveal a previously uncharacterized cross-talk of inflammatory and cell death signalling in macrophages in regulating repair processes in the skin.

immunology↗