Autoimmune Research

Autoimmune diseases are conditions caused by abnormal immune responses to functional body parts. Almost any part of the body is involved. Common symptoms may be short-lived and generally include a low-grade fever and feeling tired. The exact cause is unknown, but some autoimmune diseases, such as systemic lupus erythematosus, run in families. Some cases may be triggered by infection or other environmental factors.

Autoimmune Disease

• Celiac Disease

Celiac disease (CeD) is a common inflammatory disease of the small intestine with a prevalence between 0.5% and 2.5% in most populations of the world. CeD is a unique immune-mediated disease with well-defined necessary preconditions: exposure to nutritional gluten, the presence of human lymphocyte antigen (HLA) DQ2 or DQ8 as a key genetic predisposition, and the mechanistic involvement of the autoantigen tissue transglutaminase (TG2).

Fig.1 Main triggers and cofactors in celiac disease (CeD). (Elena, et al., 2021)

• Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD), also called Crohn's disease (CD) and ulcerative colitis (UC), are complex, multifactorial, immune-mediated disorders of the gastrointestinal tract characterized by chronic relapsing inflammation. The adaptive immune system has been considered to play the main role in the pathogenesis of IBD. Recent research in immunology has confirmed that the innate immune system maintains great importance in inducing gut inflammation. Dysfunction of the innate immune system because of abnormal signaling through immune receptors called toll-like receptors (TLRs)—which activates an immune response to molecules that are broadly shared by multiple pathogens—contributes to acute and chronic inflammatory processes in IBD colitis and associated cancer. Changes in the intestinal microbiota composition are an important environmental factor in the development of IBD.

Fig.2 Three distinct paracellular epithelial permeability pathways are disrupted during disease pathogenesis. (Matthew, et al., 2016)

• Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a systemic connective tissue disease leading to joint destruction. Initiated by an unknown antigen in genetically predisposed persons, activation of various cell types, e.g., macrophages, T- and B-lymphocytes, endothelial cells and fibroblasts, may eventually induce the characteristic changes in the synovial membrane: mononuclear cell infiltration, angiogenesis and lining cell hyperplasia. The degradation of articular cartilage, bone and ligaments is an outcome of final invasion by an activated synovial proliferating connective tissue.

Fig.3 Pathogenic Aspects of RA. (Daniel, et al., 2019)

Membrane Protein in Autoimmune Research

• MLCK

MLCK (Myosin light-chain kinase) has a well-defined mechanism of action with respect to barrier function in physiology and pathophysiology in vitro, in vivo and in patients with IBD. Additionally, studies have shown beneficial effects of MLCK inhibition in mouse models of colitis when inhibition occurs specifically in the intestinal epithelium. However, MLCK inhibition harbors potentially detrimental off-target effects due to the fact that all MLCK isoforms share a common catalytic domain. For example, smooth muscle MLCK is essential for gastrointestinal motility, blood pressure regulation and airway contractility. Although MLCK remains a promising target, more specific means of targeting long MLCK must be developed before considering MLCK as a drug target for treating human disease.

• Claudin-2

Claudin-2 offers a potentially druggable target by either modulating claudin-2 anchoring at the TJ or directly targeting dynamic claudin-2 pore open and closing events. Unfortunately, no drug for claudin-2 modulation currently exists.

• Membrane Protein in Endoplasmic Reticulum

The ER is the largest membrane-bound compartment within eukaryotic cells. This intracellular organelle has many functions, including protein and lipid synthesis, detoxification of compounds, as well as calcium storage and release. Over 30% of all cellular proteins are integrated into ER membranes or imported into the ER lumen. In addition, the ER provides quality control by regulating the proper folding and post-translational modification of secreted and membrane-bound proteins, including many key mediators of the immune response. Thus, sustaining homeostasis within the ER is essential to the survival and proper functioning of cells.

Fig.4 Drugs that Target ER Stress Pathways in RA. (Marveh, et al., 2018)

References

1. Abraham, C.; et al. Reviews in basic and clinical gastroenterology and hepatology. Gastroenterology. 2022, 162: 1602-1616.
2. Odenwald, M.A.; et al. The intestinal epithelial barrier: a therapeutic target? Nature reviews Gastroenterology & hepatology. 2017, 14: 9-21.
3. Aletaha, D.; et al. Diagnosis and Management of Rheumatoid Arthritis: A Review. Jama. 2018, 320: 1360-1372.
4. Rahmati, M. et al. ER stress: a therapeutic target in rheumatoid arthritis? Trends in Pharmacological Sciences. 2018, 39: 610-623.