Publications

A characteristic feature of autoimmune diseases is the presence of multiple antibodies. Antibody profiling can be advantageous for the early diagnosis and for a more precise classification of autoimmune diseases, for prognostic evaluation, and for disease prediction in asymptomatic subjects. Systems using micronized components (protein chips or arrays) capable of simultaneously detecting many autoantibodies at the same time are particularly suitable for testing autoantibody profiles.

• Link: https://www.sciencedirect.com/science/article/abs/pii/B9780323858311000085?via%3Dihub

HuProt Review: A characteristic feature of autoimmune diseases is the presence of multiple antibodies. Antibody profiling can be advantageous for the early diagnosis and for a more precise classification of autoimmune diseases, for prognostic evaluation, and for disease prediction in asymptomatic subjects. Systems using micronized components (protein chips or arrays) capable of simultaneously detecting many autoantibodies at the same time are particularly suitable for testing autoantibody profiles.

• Link: https://www.sciencedirect.com/science/article/abs/pii/B9780323858311000085?via%3Dihub

Tertiary lymphoid structures (TLS) are lymphoid aggregates that often form locally in tissues with chronic infection, autoimmune disease, and cancer. As such, TLS correlate with favorable prognosis in patients with solid tumors, including non-small-cell lung cancer (NSCLC). Further, TLS have recently been associated with superior response to immune checkpoint blockade (ICB). B cells are predominantly located within TLS and correlate with improved survival and ICB response. Despite the therapeutic promise of B cells and TLS, they have not been investigated as immunotherapeutic targets. Moreover, a mechanistic understanding of TLS formation and function in cancer is lacking.

• Link: https://www.jto.org/article/S1556-0864(22)01646-X/fulltext

HuProt Autoantibodies: Blood-based biomarkers can serve as a simple and cost-effective method, when used in conjunction with USPSTF guidelines, for selecting LDCT screening. Due to B-cell amplification, autoantibodies are found at a higher concentration in blood than their corresponding neoantigens, making them potentially valuable as early detection biomarkers. We hypothesize, circulating autoantibody targets can be utilized for ‘pre-screening’ individuals for LDCT testing.

• Link: https://www.jto.org/article/S1556-0864(22)01645-8/fulltext

Tertiary lymphoid structures (TLS) are lymphoid aggregates that often form locally in tissues with chronic infection, autoimmune disease, and cancer. As such, TLS correlate with favorable prognosis in patients with solid tumors, including non-small-cell lung cancer (NSCLC). Further, TLS have recently been associated with superior response to immune checkpoint blockade (ICB). B cells are predominantly located within TLS and correlate with improved survival and ICB response. Despite the therapeutic promise of B cells and TLS, they have not been investigated as immunotherapeutic targets. Moreover, a mechanistic understanding of TLS formation and function in cancer is lacking.

• Link: https://www.jto.org/article/S1556-0864(22)01646-X/fulltext#%20

HuProt Enzyme: Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether and how endolysosomal dysregulation is triggered and associated with AD. Here, we show that vacuolar ATPase (V-ATPase) is a hub that mediates proteopathy of oligomeric amyloid beta (Aβ) and hyperphosphorylated MAPT/Tau (p-MAPT/Tau). Endolysosomal integrity was largely destroyed in Aβ-overloaded or p-MAPT/Tau-positive neurons in culture and AD brains, which was a necessary step for triggering neurotoxicity, and treatments with acidic nanoparticles or endocytosis inhibitors rescued the endolysosomal impairment and neurotoxicity.

• Link: https://www.tandfonline.com/doi/full/10.1080/15548627.2023.2181614

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We sought to determine if there was antibody deposition in SAH livers and whether antibodies extracted from SAH livers were cross-reactive against both bacterial antigens and human proteins. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissue from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. Employing human proteome arrays, we profiled the antibodies extracted from explanted SAH, alcoholic cirrhosis (AC), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), hepatitis B virus (HBV)...

• Link: https://elifesciences.org/reviewed-preprints/86678

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We sought to determine if there was antibody deposition in SAH livers and whether antibodies extracted from SAH livers were cross-reactive against both bacterial antigens and human proteins. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissue from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers.

• Link: https://www.biorxiv.org/content/10.1101/2023.02.23.529702v1

Down’s syndrome (DS) presents with a constellation of cardiac, neurocognitive and growth impairments. Individuals with DS are also prone to severe infections and autoimmunity including thyroiditis, type 1 diabetes, coeliac disease and alopecia areata1,2. Here, to investigate the mechanisms underlying autoimmune susceptibility, we mapped the soluble and cellular immune landscape of individuals with DS. We found a persistent elevation of up to 22 cytokines at steady state (at levels often exceeding those in patients with acute infection) and detected basal cellular activation: chronic IL-6 signalling in CD4 T cells and a high proportion of plasmablasts and CD11c+TbethighCD21low B cells (Tbet is also known as TBX21).

• Link: https://www.nature.com/articles/s41586-023-05736-y

This chapter introduces the complex science of toxicologic pathology and highlights the critical contributions of toxicologic pathologists to drug development, through the characterization and investigation of drug-induced toxicities in nonclinical species that drive the assessment of clinical translation. Challenges are multifold and include in particular: demanding regulatory requirements, ever-increasing complexities of novel therapeutic modalities, and proliferation of molecular and computational methods providing deeper insights into toxicity mechanisms. The success and impact of toxicologic pathologists reside in their ability to discern the safety risk inherent with the target and modality, integrate in matrix organization of multidisciplinary teams, and keep up with the scientific advancements of the field.

• Link: https://www.sciencedirect.com/science/article/abs/pii/B9780128210475000336?via%3Dihub