Autoimmune diseases—where the immune system mistakenly attacks the body’s own tissues—affect over 24 million people in the U.S. alone. From rheumatoid arthritis (RA) to lupus, these conditions are often chronic, disabling, and challenging to treat. Now, researchers are turning to a little-known family of proteins called the CMTM family to unlock new insights into how these diseases develop—and how to stop them.
What Is the CMTM Family?
The CMTM (Chemokine-like factor-like MARVEL transmembrane domain-containing) family is a group of proteins discovered by scientists at Peking University. These proteins sit at the crossroads of two key immune system components: chemokines (chemical messengers that guide immune cells to sites of inflammation) and cell membrane proteins (which control how cells interact with their environment).
CMTM proteins are widely expressed in immune cells—including T lymphocytes, B cells, and neutrophils—and play roles in cell communication, activation, and migration. The family includes 9 members: CKLF1 (the first discovered) and CMTM1 to CMTM8. For years, researchers have suspected these proteins are linked to autoimmune diseases, but recent studies are starting to prove it.
CKLF1: The Most Studied CMTM Member
CKLF1 (Chemokine-like factor 1) is the best-understood CMTM protein—and a major player in autoimmune inflammation. Found on chromosome 16, CKLF1 binds to the CCR4 receptor (a “landing pad” for immune cells like T helper cells and dendritic cells). When CKLF1 attaches to CCR4, it triggers three key processes:
- Immune cell activation: CKLF1 boosts T cell activity (a hallmark of autoimmune diseases like RA).
- Inflammation: It increases production of pro-inflammatory molecules (e.g., TNF-α, IL-1β) and adhesion proteins that let immune cells stick to blood vessels.
- Cell migration: CKLF1 draws immune cells to tissues—like joints in RA or kidneys in lupus—where they cause damage.
CKLF1 and Specific Diseases
- Lupus nephritis: High CKLF1 levels in lupus patients correlate with more severe kidney inflammation and higher urine protein (a sign of kidney damage). Animal studies show that reducing CKLF1 lessens lupus-related kidney harm.
- Rheumatoid arthritis: CKLF1 is overexpressed in the synovium (the lining of joints) of RA patients. It promotes inflammation, blocks cartilage repair, and correlates with markers of disease activity like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).
- Psoriasis: CKLF1 and CCR4 are highly expressed in psoriatic skin lesions. CKLF1 drives the growth of skin blood vessels and activates the MAPK/ERK pathway—a key driver of skin cell overgrowth in psoriasis.
Other CMTM Members and Autoimmune Diseases
While CKLF1 gets the most attention, other CMTM proteins are also linked to autoimmune conditions:
- CMTM1: Linked to RA through calcium signaling. A drug called celastrol (used in traditional medicine) reduces CMTM1 levels in RA synovial cells, which may help calm inflammation.
- CMTM2: Downregulated in osteoarthritis (OA) bone marrow lesions and differentially expressed in systemic sclerosis (SSc)—a disease marked by skin and organ fibrosis.
- CMTM3: Found at high levels in B cells and monocytes. It’s a potential biomarker for Sjögren’s syndrome (a disease that dries out saliva and tear glands).
- CMTM4/CMTM5: Associated with lupus through epigenetic changes (how genes are turned on or off). CMTM4 promoter methylation (a chemical “switch” that silences genes) is altered in lupus, RA, and Sjögren’s.
- CMTM6: Upregulated in neutrophils of people with antiphospholipid syndrome (APS), a disorder that causes blood clots and pregnancy complications. Neutrophils in APS release “NETs” (web-like structures that trap pathogens but also trigger clots)—CMTM6 may fuel this process.
Why CMTM Proteins Matter for Treatment
The CMTM family is a promising target for new autoimmune therapies. Unlike broad immunosuppressants (which weaken the entire immune system), targeting CMTM proteins could be precise:
- Anti-CKLF1 drugs: Blocking CKLF1 or its interaction with CCR4 might reduce joint inflammation in RA or kidney damage in lupus.
- Epigenetic therapies: Drugs that reverse CMTM4/CMTM5 methylation could help regulate immune responses in lupus.
- Biomarkers: CMTM levels (e.g., CKLF1 in blood or synovial fluid) could serve as early warning signs for disease flares or treatment response.
What’s Next?
Much is still unknown about the CMTM family—especially CMTM7 and CMTM8, which are mostly studied in cancer and heart disease. But the research so far makes one thing clear: these proteins are not just “background players” in the immune system—they’re drivers of autoimmune disease.
For millions living with conditions like RA, lupus, or psoriasis, this research offers hope. By decoding how CMTM proteins work, scientists are moving closer to treatments that target the root cause of autoimmune diseases—rather than just masking symptoms.
This study was conducted by Hong-Ji Duan, Xin-Yi Li, Chang Liu, and Xiao-Li Deng from the Department of Rheumatology and Immunology at Peking University Third Hospital, Beijing. It was funded by the National Natural Science Foundation of China (grant number 81501390). The authors declare no conflicts of interest.
doi.org/10.1097/CM9.0000000000000747
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