Can low total IgG coexist with autoimmunity and recurrent infections?

Low total IgG and autoimmunity are not contradictory findings, particularly in common variable immunodeficiency (CVID), where defective humoral immunity can coexist with substantial immune dysregulation.

Clinical and mechanistic evidence

• CVID is characterized by reduced IgG and impaired specific antibody responses, yet autoimmunity occurs in approximately 20–50% of patients across cohorts, with autoimmune cytopenias among the prominent manifestations.
• Autoimmune CVID cohorts show increased autoreactive 9G4-positive B cells in naïve and memory compartments, supporting failures of both central and peripheral B-cell tolerance. Reduced switched-memory B cells are also associated with autoimmunity and other non-infectious CVID complications.
• Proposed mechanisms include impaired deletion of autoreactive B cells and, in some people with TNFRSF13B/TACI variants, altered B-cell-receptor–TLR7/9 signaling. Expansion of CD21low B cells may further reflect an autoreactive/polyreactive B-cell compartment, although it is not universal or diagnostic alone.
• Thus, low bulk immunoglobulin production does not imply absence of pathogenic autoreactive B cells. Defects in class switching, affinity maturation, activation, and plasma-cell differentiation may coexist with failed immune tolerance.

Infection and inflammatory implications

• Low IgG is credibly associated with greater vulnerability to recurrent, severe, or persistent infection. In adults receiving rituximab for systemic autoimmune rheumatic disease, baseline IgG <6 g/L was associated with greater severe-infection risk; in transplant studies, IgG <4 g/L was associated with respiratory, CMV, and fungal infections.
• Reduced neutralization, opsonization, complement activation, and phagocyte-mediated clearance provide a direct explanation. Persistent microbial antigen exposure can plausibly sustain innate receptor signaling and inflammatory cytokine production, although this downstream systemic effect is conditional rather than established in humans with hypogammaglobulinemia.

Bottom line

• Low IgG can coexist with—and does not protect against—autoimmunity; it also increases infection susceptibility. Infection-driven ongoing immune stimulation is biologically plausible, while its direct contribution to systemic immune dysregulation remains less firmly demonstrated.