CA2 antibodies target carbonic anhydrase II (CA-II), an enzyme critical for pH regulation, fluid secretion, and bone resorption. CA-II catalyzes the reversible hydration of carbon dioxide to bicarbonate and protons, playing roles in renal acid excretion, osteoclast-mediated bone remodeling, and other physiological processes. Autoantibodies against CA-II are primarily studied in autoimmune and inflammatory disorders. They are notably associated with autoimmune pancreatitis, Sjögren’s syndrome, and systemic lupus erythematosus (SLE), where their presence may reflect epitope spreading or molecular mimicry triggered by infections or tissue damage. In autoimmune pancreatitis, CA-II antibodies are proposed to cross-react with plasminogen-binding protein of *Helicobacter pylori*, suggesting a pathogenetic link. However, their diagnostic specificity remains limited, as they are also detected in non-autoimmune conditions like rheumatoid arthritis and chronic liver diseases. Research highlights CA-II antibodies' potential role in disrupting cellular homeostasis, particularly in tissues rich in CA-II, such as renal tubules and salivary glands. While not a standalone diagnostic marker, their detection complements broader autoantibody profiles (e.g., ANA, anti-SSA/SSB) in evaluating autoimmune etiologies. Further studies aim to clarify their pathogenic mechanisms and clinical utility in disease stratification or monitoring.