Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease associated with cholangiopathies. The detection of antimitochondrial autoantibodies (AMAs) plays an important role in the diagnosis of classical PBC. AMAs are formed against the antigenic component associated with the dihydrolipoyl transacetylase of pyruvate dehydrogenase complex (E2 PDC) localized on the inner membrane of mitochondria. The loss of immune tolerance of E2 PDC in PBC is thought to be the cause of the mechanism of AMA formation and immune-mediated destruction of biliary epithelial cells (BECs) of the small- and medium-sized intrahepatic bile ducts. E2 PDC is not only present in BECs, but is also abundant in the mitochondria of all nucleated cells. The question remains as to why E2 PDC of only small BECs is the target of autoimmune attack. There is no evidence that AMAs have a deleterious effect on BECs. New scientific data has emerged that explains the damage to BECs in PBC by the defect of the biliary bicarbonate (HCO₃^–) “umbrella” that protects BECs from the detergent action of bile acids under physiological conditions. Disruption of HCO₃^– production by BECs in PBC leads to changes in the pH of hepatic bile, accompanied by accumulation of bile acids in the small BECs. The detergent action of bile acids leads to damage of membrane structures of BECs and their apoptosis, development of ductulopenia, and intrahepatic cholestasis. For the first time, it has been suggested that under the influence of bile acids, the E2 PDC antigen may undergo conformational changes that alter its immunological properties. E2 PDC becomes a neoantigen that is recognized by the normal (“healthy”) immune system as a foreign antigen, leading to the production of AMAs. For the first time, the authors of this review provide an explanation for why only small BECs are damaged in PBC.

Rheumatoid arthritis (RA) is a complex autoimmune disorder characterized by a spectrum of hypersensitivity reactions, encompassing Type II, Type III, and Type IV responses. Firstly, RA is marked by Type II hypersensitivity reactions driven by autoantibodies, such as rheumatoid factor (RF) and anti-(cyclic) citrullinated protein antibodies (ACPAs). These autoantibodies serve not only as serological markers for RA but also actively participate in inflammation, bone erosion, and clinical outcomes, with concurrent activation of the complement system involving C1q, C3, and C5 components specifically linked to RA progression and bone damage. Secondly, RA exhibits traits of Type III hypersensitivity, marked by the formation of immune complexes inciting inflammatory reactions. Immunoglobulin G (IgG) autoantibodies like RF and ACPA play pivotal roles in immune complex formation and the ensuing inflammatory responses. RA also demonstrates Type IV hypersensitivity propelled by CD4⁺ T cells, encompassing T helper 1 (Th1) and Th17 subsets. Th1 cells release interferon (IFN)-γ, promoting proinflammatory cytokines, while Th17 cells secrete IL-17, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF), contributing to synovial inflammation, bone and cartilage damage, and angiogenesis. RA concurrently exhibits features of Type II, Type III, and Type IV hypersensitivity. It is crucial to comprehend the presence and complex interplay of hypersensitivity responses and specific immune cell subsets in RA to create precise and efficient therapeutic approaches for the management of this incapacitating autoimmune condition. Thus, in this review, we aim to provide a comprehensive overview of the hypersensitivity features of RA.

Adaptor proteins are involved in various immune responses via the modulation of many signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that contains typical domains such as the pleckstrin homology (PH) domain, Src homology domain, and a proline-rich region from the N-terminal region. In T cells, STAP-2 positively regulates T cell receptor (TCR)-mediated signaling by associating with CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (LCK). Therefore, a peptide that inhibits the interaction between STAP-2 and CD3ζ ITAMs is likely to suppress TCR-mediated T cell activation, as well as T cell-mediated diseases. As expected, the peptide successfully inhibited the STAP-2/CD3ζ ITAM interaction and suppressed TCR-mediated signaling, cell proliferation, and interleukin (IL)-2 production in human/murine T cells. Furthermore, this inhibitor suppressed the pathogenesis of experimental autoimmune encephalomyelitis (EAE), which is widely recognized as a mouse model of multiple sclerosis, via the downregulation of T cell activation and infiltration of T helper (Th) 1/Th17 cells. These results suggest a new strategy for the treatment of multiple sclerosis and other immune diseases.