Abstract
DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.
Highlights
Autoimmune diseases are complex and multifaceted disorders
To characterize the eluted peptides for affinity comparison, the Immune Epitope Database (IEDB) algorithm [37,38] was applied, which revealed that, globally, peptides from DO-WT B cells were predicted to be of higher affinity for binding to I-Ab than peptides eluted from DO-KO B cells (Fig 1B top)
Because of the finding that peptides eluted in the absence of DO appear to be of lower affinity, it is likely that the observed lower percentage of unique DO-KO–derived peptides might be due to lower abundance, causing a disproportionate loss during sample preparations, failure of mass spectrometry to detect them
Summary
Autoimmune diseases are complex and multifaceted disorders. While extensive research has gone into understanding the underlying causes of various autoimmune pathologies, one of the first risk factors described was the Major Histocompatibility Complex (MHC) loci in disease development [1,2]. A main risk factor to developing such autoimmune conditions as: rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CD) are specific MHC class II alleles (RA/T1D: HLA-DR1, CD: HLA-DQ2.5/8) [3]. Much remains unknown as to why certain MHC II alleles associate with these autoimmune diseases. To explore the answer to this question, major research efforts have been invested into understanding the MHC class II processing pathway. Among all the components in the MHC class II processing pathways, two highly conserved nonclassical class II accessory molecules, DM (HLA-DM human; murine H2-M) and DO, are directly involved in the regulation and editing
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