**2. The novel function of HLA class II molecules and autoimmune diseases**

The classical function of HLA class II molecules is to present antigen peptides, derived from exogeneous proteins digested in lysosomes, to helper T-cells and by that to activate them.

Endogenous proteins, on the other hand, are formed and folded in the endoplasmic reticulum (ER). Correctly folded proteins are essential for cell survival and function. Therefore, it is believed that misfolded proteins generated in the ER are never transported to the extracellular space, because such proteins are eliminated by ER-associated degradation (ERAD).

However, Arase *et al.* discovered that misfolded proteins can be rescued from ERAD and transported to the cell surface without being processed into peptides. This process occurs in the ER via an association between the misfolded proteins and the peptide-binding groove of HLA class II molecules [2].

In addition, misfolded proteins complexed with HLA class II molecules of disease-susceptible alleles have been found to serve as targets of autoantibodies in certain autoimmune diseases, and to be involved in the disease pathogenesis. For example, immunoglobulin (Ig) G heavy chain complexed with HLA-DR and myeloperoxidase complexed with HLA-DR are major targets for autoantibodies in patients with rheumatoid arthritis and microscopic polyangiitis, respectively [3, 5].
