Review

Authors: Peter J Eggenhuizen, Boaz H Ng, Joshua D Ooi...

Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

Topics: Adoptive Transfer; Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance; Nanoparticles; T-Lymphocytes, Regulatory

PubMed: 32977677
DOI: 10.3390/ijms21197015

Review

Authors: Yangdan Liu, Chiakang Ho, Dongsheng Wen...

The skin epidermis and appendages undergo ongoing renewal throughout life. Stem cells residing in the epidermis and hair follicles are pivotal for sustaining skin homeostasis. The self-renewal ability of stem cells significantly decreases during skin aging but actively increases during wound repair. Residential stem cells reside in niches that provide spatially distinct microenvironments for stem cell maintenance and function. Cell-extracellular matrix (ECM) adhesion is essential for the establishment of niche architecture. Collagen XVII (COL17), as a transmembrane protein constituting hemidesmosomes (HDs), mediates the interactions of stem cells with surrounding cells and the matrix to regulate skin homeostasis, aging and wound repair. This review focuses on the pivotal role of the niche component COL17 in stem cell maintenance and its function in regulation of skin aging and wound repair.

Topics: Autoantigens; Non-Fibrillar Collagens; Skin Aging; Stem Cell Niche; Collagen Type XVII

PubMed: 36185608
DOI: 10.7150/thno.78016

Review

Authors: Sandra G Williams, Sandra L Wolin

Although autoimmunity and autoimmune disease (AID) are relatively common, the repertoire of autoantigens is paradoxically very limited. Highly enriched in this autoantigen repertoire are nucleic acids and their binding proteins, which together form large macromolecular structures. Most of these complexes are of ancient evolutionary origin, with homologs throughout multiple kingdoms of life. Why and if these nucleic acid-protein particles drive the development of autoimmunity remains unresolved. Recent advances in our understanding of the microbiome may provide clues about the origins of autoimmunity - and the particular puzzle of why the autoantigen repertoire is so particularly enriched in ribonucleoprotein particles (RNPs). We discuss the possibility that autoimmunity to some RNPs may arise from molecular mimicry to microbial orthologs.

Topics: Autoantigens; Autoimmune Diseases; Autoimmunity; Genes, Bacterial; Humans; Immunity; Microbiota; Molecular Mimicry; Ribonucleoproteins

PubMed: 33722441
DOI: 10.1016/j.molmed.2021.02.003

Review

Authors: Sho Hiroyasu, Christopher T Turner, Katlyn C Richardson...

Pemphigoid diseases are a subgroup of autoimmune skin diseases characterized by widespread tense blisters. Standard of care typically involves immunosuppressive treatments, which may be insufficient and are often associated with significant adverse events. As such, a deeper understanding of the pathomechanism(s) of pemphigoid diseases is necessary in order to identify improved therapeutic approaches. A major initiator of pemphigoid diseases is the accumulation of autoantibodies against proteins at the dermal-epidermal junction (DEJ), followed by protease activation at the lesion. The contribution of proteases to pemphigoid disease pathogenesis has been investigated using a combination of and models. These studies suggest proteolytic degradation of anchoring proteins proximal to the DEJ is crucial for dermal-epidermal separation and blister formation. In addition, proteases can also augment inflammation, expose autoantigenic cryptic epitopes, and/or provoke autoantigen spreading, which are all important in pemphigoid disease pathology. The present review summarizes and critically evaluates the current understanding with respect to the role of proteases in pemphigoid diseases.

Topics: Autoantibodies; Autoantigens; Dermis; Epidermis; Humans; Pemphigoid, Bullous; Peptide Hydrolases

PubMed: 31297118
DOI: 10.3389/fimmu.2019.01454

Authors: Peter J Eggenhuizen, Rachel M Y Cheong, Cecilia Lo...

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Topics: Mice; Animals; Humans; Lupus Nephritis; T-Lymphocytes, Regulatory; Lupus Erythematosus, Systemic; Autoantigens

PubMed: 38321013
DOI: 10.1038/s41467-024-45056-x

Review

Authors: Jussi Tuusa, Nina Kokkonen, Kaisa Tasanen...

BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein-protein interactions.

Topics: Autoantigens; Hemidesmosomes; Humans; Keratinocytes; Non-Fibrillar Collagens; Pemphigoid, Bullous; Protein Folding; Collagen Type XVII

PubMed: 34830116
DOI: 10.3390/ijms222212233

Review

Authors: F Leypoldt

There is a need to improve therapies in autoimmune neurologic conditions. Yet which strategic objectives are required, what are the barriers that stand before reaching them, and what are the options to address them? This article tries to summarize these objectives and their respective barriers. It discusses the difficulties in identifying molecular targets, biomarker-defined subgroups, the merits of upstream and downstream-targeted therapies, the need to develop autoreactivity-specific treatments in contrast to cell-type specific therapies, and the "evidence-bottleneck". Its focus is on autoantigen-specific autoimmunopathies in neurology. It also discusses the role of B- and T-cells in autoimmune neurology and how these can be exploited therapeutically. Finally, it argues for improved training of present and future neuroimmunologists.

Topics: Humans; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Autoimmune Diseases; Autoantigens

PubMed: 39299843
DOI: 10.1016/j.neurol.2024.08.005

Authors: Sara E Vazquez, Sabrina A Mann, Aaron Bodansky...

Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

Topics: Humans; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacteriophages; COVID-19; Homeodomain Proteins; Immunoprecipitation; Proteome

PubMed: 36300623
DOI: 10.7554/eLife.78550

Authors: Yihan Lin, Zurong Wan, Bo Liu...

Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical segregation from their cognate autoantigen. Unexpectedly, we find that follicular B cell-derived autoantigen, including cell surface molecules such as FcγRIIB, is a class of homeostatic autoantigen that can induce spontaneous germinal centers (GCs) and B cell-reactive autoantibodies in non-autoimmune animals with intact T and B cell repertoires. These B cell-reactive B cells form GCs in a manner dependent on spontaneous follicular helper T (T) cells, which preferentially recognize B cell-derived autoantigen, and in a manner constrained by spontaneous follicular regulatory T (T) cells, which also carry specificities for B cell-derived autoantigen. B cell-reactive GC cells are continuously generated and, following immunization or infection, become intermixed with foreign antigen-induced GCs. Production of plasma cells and antibodies derived from B cell-reactive GC cells are markedly enhanced by viral infection, potentially increasing the chance for autoimmunity. Consequently, immune homeostasis in healthy animals not only involves classical tolerance of silencing and ignoring autoreactive B cells but also entails a reactive equilibrium attained by a spontaneous B cell-reactive triad of B cells, T cells and T cells.

Topics: Animals; T-Lymphocytes, Regulatory; T-Lymphocytes, Helper-Inducer; B-Lymphocytes; Germinal Center; Autoantigens

PubMed: 38326478
DOI: 10.1038/s41422-024-00929-0

Authors: Antony Rosen

The striking association of specific autoantibodies with distinct disease phenotypes and trajectories in human autoimmune rheumatic diseases provides a powerful opportunity to interrogate disease mechanism. In scleroderma, a subgroup of patients with autoantibodies to POLR3 have coincident onset of cancer and scleroderma. The majority of these patients have genetic changes (somatic mutations and loss of heterozygosity) in the POLR3A gene in their matched cancers, coupled with immune responses directed against the mutated and wild type autoantigen. In some individuals with scleroderma or dermatomyositis where specific immune responses mark a high risk of emergent cancer, cancer does not emerge. Such patients have a broader immune response that targets additional autoantigens, suggesting that the breadth and magnitude of the immune response regulates cancer, and that the rheumatic diseases provide a unique window into natural immunoediting of cancer in humans. This has implications for prediction and therapy in both autoimmunity and cancer.

Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Humans; Neoplasms; RNA Polymerase III; Rheumatic Diseases

PubMed: 36196176
DOI: No ID Found