SEATTLE — The genetic vulnerability to psoriasis and related autoimmune diseases may be traceable to evolutionary pressure to resist ancient infections by retroviruses. The theory is that variations in major histocompatibility complex class 1 (MHC-1) proteins, which play a key role in presenting pathogen-derived peptides to CD8+ T cells, may have improved the immune response against these viral scourges and thus became widespread in the human genome.
But they may also carry a cost. At least 12 separate genetic variations of MHC-1 proteins have been linked to an increased risk for psoriasis, according to work performed by Wilson Liao, MD, who gave a presentation on the topic at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2024 annual meeting and Trainee Symposium. The thought is that psoriasis may be just one of a group of autoimmune diseases that trace their roots to variations in MHC-1 and peptide processing genes. These diseases, sometimes referred to as MHC-1-opathies, include spondyloarthritis, Behcet disease, and birdshot uveitis.
The proposed MHC-1-opathies share several other characteristics: They affect epithelial, mucosal, or mechanically affected tissues; they involve activation of CD8+ T cells; and they are often associated with upregulation of the interleukin (IL) 23, IL-17, or tumor necrosis factor cytokines, according to Liao.
“Historically, the top allele associated with psoriasis is HLA-C*06:02, but what’s not generally recognized is that if you adjust for the effect of HLA-C*06:02 in conditional analyses, you can identify other HLA alleles that are associated with psoriasis as well,” said Liao, professor and associate vice chair of research and director of the Psoriasis and Skin Treatment Center, University of California, San Francisco.
The question is how these variations might influence MHC-1-opathies. Studies have been done on individuals infected with HIV-1 who progress to AIDS more slowly than average, sometimes never developing AIDS, even without antiretroviral therapy, he said. Researchers have identified four different protective mechanisms that stem from separate variations in the human leukocyte antigen (HLA)-A and HLA-B regions of MHC-1, as well as changes that affect HLA regulation of natural killer cells and dendritic cells. There are also unfavorable variations associated with more rapid progression to AIDS, such as HLA-B-35.
An analysis by Liao’s group of peptides involved in AIDS resistance found specific peptides that were protective, and an analysis of genetic variations associated with greater psoriasis risk found that the same peptides, in the same positions within the HLA-B protein, were linked to greater risk. HLA-B-35 confers a faster progression to AIDS but is associated with reduced risk for psoriasis.
Additionally, the researchers observed that very high levels of HLA-C expression are beneficial, likely because of increased levels of antigen presentation, said Liao. These increased levels can occur because of a deletion variant, and researchers found that the same deletion variant leads to a higher risk for psoriasis.
A third mechanism involves an interaction between MHC-1 and natural killer cells through killer cell immunoglobulin-like receptors (KIRs). Individuals with HIV-1 who have both the KIR3DS1 variant and the Bw4 HLA-B variant may be protected against psoriasis, though either variant alone has no apparent effect. Similarly, the combination of variants is associated with a fourfold increased risk for psoriasis, whereas either variant alone has no association.
A fourth mechanism involves leukocyte immunoglobulin-like receptors (LILRs) on MHC-1 that can either upregulate or downregulate dendritic cells. The variant LILRB2, which is linked to inhibition of dendritic cells, works in combination with HLA-B to downregulate the inhibitory receptor and ultimately increase activation of T cells. Again, this combination is associated with a heightened risk for psoriasis.
“So there is this interesting, remarkable similarity between psoriasis patients and those who are HIV-1 controllers. What does this all mean? I think it provides a theoretical framework for why we have psoriasis or autoimmune diseases,” said Liao. “Over the course of evolution, our immune systems were regarded by various pathogens, including retroviruses, and there’s likely a positive selection mechanism by which certain alleles are beneficial in defending against these various viruses. However, if those alleles are aberrantly activated in the skin or the joints or other tissues, you may develop an autoimmune disease like psoriasis.”
“It also reaches an intriguing hypothesis that perhaps antigenic triggers in MHC-1-opathies could involve viral or virus-like particles. About 8% of our own genome are human endogenous retroviruses that have integrated into our genome, and many of these are actually expressed. So could there be something internally that’s being presented and triggering these MHC-1-opathies?” Liao asked.
During the Q&A session, an audience member asked Liao if his hypothesis suggested that interferon inhibitors could be a potential treatment for psoriasis. “It’s a great question. I think there are different endotypes or flavors of psoriasis, some of which may be more interferon driven, and some of which [are related to IL-17]. A lot of folks are doing molecular phenotyping to see what type of psoriasis the patient has, and then picking either a broad-spectrum oral agent or a more targeted inhibitor,” said Liao.
Liao reported no disclosures or funding sources.
Source link : https://www.medscape.com/viewarticle/mhc-1-opathies-linked-ancient-retrovirus-infections-2024a1000dnt?src=rss
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Publish date : 2024-07-25 03:11:00
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