Biomedical subjects

Baktiar Karim

Publications and source records attributed to Baktiar Karim.

3 recordsLinked to original sources

PubMed2026

Distributed clonal deletion prevents autoimmune disease progression.

Self-reactive B cells arise during development and can increase pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification. 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 self-tolerance is enforced through temporally distinct mitochondrial outer membrane permeabilization (MOMP) checkpoints. Using conditional Bcl-2 expression to inhibit MOMP either from B cell development or activation, we find that early inhibition permits survival of autoreactive B cells after peripheral egress, expanding the pool available for activation and AID-dependent diversification. This results in broadened class-switched IgG autoreactivity, complement activation, kidney pathology, and drives lethal autoimmune disease. In contrast, post-activation MOMP inhibition promotes autoreactive cell accumulation and autoantibody production but causes limited tissue damage and normal survival. Together, these findings support a Distributed Clonal Deletion Model in which temporally distinct checkpoints cooperate to constrain autoimmune disease progression.

AID↗

PubMed2026

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.

Journal Article↗

PubMed2025

The elevated expression of ORF75, a KSHV lytic gene, in Kaposi sarcoma lesions is driven by a GC-rich DNA cis element in its promoter region.

The spindle cells of Kaposi sarcoma (KS) lesions primarily express Kaposi sarcoma herpesvirus (KSHV) latent genes with minimal expression of lytic genes. However, recent transcriptome analyses of KS lesions have shown high expression of KSHV open reading frame (ORF) 75, which is considered a late lytic gene based on analyses in primary effusion lymphoma (PEL) lines. ORF75 encodes a pseudo-amidotransferase that is part of the viral tegument, acts as a suppressor of innate immunity, and is essential for viral lytic replication. We assessed a representative KS lesion by RNAscope and found that ORF75 RNA was expressed in the majority of latency-associated nuclear antigen (LANA)-expressing cells. Luciferase fusion reporter constructs of the ORF75 promoter were analyzed for factors potentially driving its expression in KS. The ORF75 promoter construct showed high basal transcriptional activity in vitro in endothelial cells, mediated by a proximal consensus specificity protein 1 (Sp1) (GGGGCGGGGC) element along with two distal CCAAT boxes. Sp proteins formed complexes with the proximal consensus Sp1 element to activate ORF75 promoter transcription. We also found evidence that a repressive factor or factors in B cells, but not endothelial or epithelial cells, interacted with more distal elements in the ORF75 promoter region to repress constitutive ORF75 expression in B cells. Alternate forms of Sp1 were found to accumulate during latency and showed substantial enrichment during viral lytic replication in PEL cells and infected endothelial cells, but their functional significance is unclear. We also found that ORF75 can in turn upregulate its own expression and that of other KSHV genes. Thus, while ORF75 acts primarily as a lytic gene in PEL cell lines, Sp proteins induce substantial constitutive ORF75 transcription in infected endothelial cells and this can account for its high expression in KS lesions.

Herpesvirus 8, Human↗