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

Abstract

The diagnosis of immunoglobulin G4 (IgG4)-related autoimmune neuropathies relies on a combination of clinical evaluation, imaging, and biological analyses, including serum and cerebrospinal fluid assessments. Several IgG4 autoantibodies have been described in these disorders, including muscle-specific kinase IgG4, leucine-rich glioma-inactivated 1 IgG4, nodo-paranodal IgG4, Ig-like domain-containing protein 5, anti-dipeptidyl-peptidase-like protein-6 antibodies, and contactin-associated protein-like 2 IgG4. Accurate identification of these autoantibodies using appropriate techniques is essential for optimizing diagnosis and guiding treatment selection. In addition, specific human leukocyte antigen (HLA) alleles and haplotypes are associated with the induction of these autoantibodies. This review summarizes current knowledge on the role of HLA alleles in regulating IgG4 autoantibody production and examines methods for detecting these autoantibodies, as well as their diagnostic and prognostic significance in IgG4-mediated neurological disorders.

Keywords: Human leukocyte antigen; Immunoglobulin G4 autoantibodies; Autoimmunity; Neurological diseases; Autoimmune neurological diseases

Core Tip: Human leukocyte antigen (HLA) class II molecules present peptides derived from neuronal and glial membrane proteins to CD4+ T cells, particularly follicular helper T cells and interleukin (IL)-10-producing regulatory subsets. In the IL-10-rich milieu associated with chronic antigen exposure, B cells undergo immunoglobulin G4 (IgG4) class switching and differentiate into high-affinity plasma cells and memory cells, thereby driving the production of pathogenic IgG4 neuro-autoantibodies. These antibodies disrupt protein-protein interactions rather than inducing classical inflammatory responses. IgG4 neuro-autoantibodies are mainly detected in serum and cerebrospinal fluid using cell-based assays, although these assays are labor-intensive and require specialized cell culture and transfection facilities. HLA typing may have clinical relevance in patients with intrathecal IgG4 antibodies and may help explain specific phenotypic associations in anti-Ig-like domain-containing protein 5 disease, including the increased frequency of sleep and bulbar manifestations. Distinct HLA associations also underlie the divergent clinical profiles observed in leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2 antibody diseases.