Clinical utility of human leukocyte antigen genotyping and immunoglobulin G4 autoantibody testing in autoimmune neurological diseases: A focused minireview

Figure 1 Role of human leukocyte antigen class II in immunoglobulin G4 antibody responses in autoimmune neurological diseases. A: Production of IgLON5 autoantibodies; B: Production of immunoglobulin G4 (IgG4) muscle-specific kinase autoantibodies; C: Production of IgG4 anti-NF155 autoantibodies. Human leukocyte antigen (HLA) class II molecules bind peptides derived from neuronal and glial membrane proteins (such as IgLON5, muscle-specific kinase, and neurofascin-155) that are endocytosed by antigen-presenting cells, and present them for recognition by CD4+ T cells, particularly follicular helper T (Tfh) cells and interleukin (IL)-10-producing regulatory subsets. B cell activation requires both binding of the antigen to the B cell receptor complex (signal 1) and interaction of the B cell with antigen-specific helper T cells (signal 2). In an IL-10-rich microenvironment characteristic of chronic antigen exposure, B cells undergo class switching to IgG4 and differentiate into high-affinity antibody-secreting cells as well as memory cells, which play an important role in the production of pathogenic IgG4 neuro-autoantibodies. AutoAbs: Autoantibodies; IgLON5: Ig-like domain-containing protein 5 (neuronal cell adhesion protein); HLA-II: Human leukocyte antigen class II molecules; TCR: T-cell receptor; BCR: B-cell receptor; Tfh: Follicular helper T cells; IL-4: Interleukin-4; IL-10: Interleukin-10; IL-13: Interleukin-13; Fab: Fragment antigen-binding.

Figure 2 Pathogenic mechanisms of immunoglobulin G4 autoantibodies. Immunoglobulin G4 (IgG4) autoantibodies can mediate autoimmune neurological diseases through distinct mechanisms: A: Anti-Ig-like domain-containing protein 5 (IgLON5) IgG4 antibodies bind to neuronal surface IgLON5 (predominantly expressed in hypothalamic and brainstem regions), triggering acute neuronal hyperactivity that may subsequently lead to tau hyperphosphorylation and accumulation as a downstream neurodegenerative process; B: IgG4 antibodies against muscle-specific kinase (MuSK) block interactions with low-density lipoprotein receptor-related protein 4 and collagen Q, impairing synaptic transmission and acetylcholine receptor clustering in MuSK-related myasthenia gravis; C: IgG4 anti-neurofascin 155 (NF155) antibodies disrupt paranodal axo-glial junctions by interfering with NF155-Caspr1/CNTN1 interactions, leading to paranodal detachment in chronic inflammatory demyelinating polyradiculoneuropathy. AutoAbs: Autoantibodies; IgLON5: Ig-like domain-containing protein 5 (cell adhesion protein); p-tau: Phosphorylated tau protein; MuSK: Muscle-specific kinase; AChR: Acetylcholine receptor; LRP4: Low-density lipoprotein receptor-related protein 4; Col-Q: Collagen Q (collagen-like tail subunit of asymmetric acetylcholinesterase); Ach: Acetylcholine; AChE: Acetylcholinesterase; Agrin: Agrin (proteoglycan involved in neuromuscular junction formation); MG: Myasthenia gravis; NF155: Neurofascin 155; Caspr1: Contactin-associated protein 1; CNTN1: Contactin 1; Nav: Voltage-gated sodium channel; Kv: Voltage-gated potassium channel; CIDP: Chronic inflammatory demyelinating polyneuropathy.