Possible Effects of the CMTM Family on Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a hidden but impactful autoimmune disease: it causes blood clots (thrombosis) or pregnancy complications (like recurrent miscarriages or premature birth) in people with persistent antiphospholipid antibodies (aPLs). While aPLs are key to APS, they aren’t the whole story—research shows immune cells, inflammation, and cellular signaling play critical roles too. Now, a growing body of work suggests a family of genes called the Chemokine-like Factor-like MARVEL Transmembrane Domain-Containing (CMTM) family could be a missing piece in understanding APS.

In a 2021 review published in the Chinese Medical Journal, researchers Ying-Ying Ge, Hong-Ji Duan, and Xiao-Li Deng (from Peking University Third Hospital’s Rheumatology and Immunology Department) systematically analyzed how CMTM proteins interact with APS pathways. Their work highlights CMTM’s potential as a new target for diagnosis or treatment—and offers fresh insights into why some people with aPLs develop APS while others don’t.

What Is Antiphospholipid Syndrome (APS)?

APS is defined by two things:

Clinical symptoms: Blood clots (in veins or arteries) or obstetric issues (recurrent early abortion, fetal loss, or preterm birth from placental problems).
Serologic hallmark: Persistently high levels of aPLs—specifically lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein I (anti-β2GPI) antibodies.

APS can occur alone (“primary APS”) or alongside other autoimmune diseases like systemic lupus erythematosus (SLE). The problem? aPLs aren’t enough to cause symptoms—something else triggers the body’s pro-inflammatory, pro-thrombotic response. That’s where the immune system and CMTM come into play.

Meet the CMTM Family: A Hidden Player in Immunity

The CMTM family is a group of 9 genes (CKLF + CMTM1–8) first identified by Peking University researchers in 2001. These genes make proteins that sit on cell membranes or float in the blood, acting as chemokines (molecules that attract immune cells) or transmembrane proteins (molecules that help cells communicate).

Key facts about CMTM:

Location: Genes are clustered on three chromosomes (16q22.1, 14q11.2, and 3p23).
Function: CMTM proteins regulate immune cell activity, cell-to-cell adhesion, and signaling pathways—all critical for autoimmune diseases like APS.
Diversity: Each CMTM member has a unique role. For example, CKLF1 (Chemokine-like Factor 1) is a potent chemokine, while CMTM7 helps B-cells (antibody-making cells) function.

How Does the CMTM Family Interact With APS?

APS pathogenesis hinges on three main processes: endothelial cell activation (damage to blood vessel linings), immune cell dysfunction (overactive neutrophils, T-cells, or B-cells), and platelet activation (blood clot formation). The CMTM family touches all three.

1. Endothelial Cells: Keeping Blood Vessels Healthy

Endothelial cells line blood vessels—when activated by aPLs, they release pro-inflammatory molecules (like TNF-α) and sticky adhesion proteins (like ICAM-1), setting the stage for clots.

CKLF1: This CMTM protein increases inflammation by activating the NF-κB pathway (a key driver of pro-inflammatory genes). Studies show anti-CKLF1 antibodies reduce TNF-α, IL-1β, and adhesion molecules—suggesting CKLF1 could be a target to calm overactive endothelium.
CMTM3: Helps maintain the “barrier” function of endothelial cells by regulating VE-cadherin (a protein that keeps cells tightly joined). When CMTM3 is low, endothelial cells become leaky—promoting inflammation and clotting.

2. Platelets: The Clotting Connection

Platelets are tiny cells that form clots to stop bleeding—but in APS, aPLs make them overactive. CMTM proteins like CMTM3, CMTM5, and CMTM7 are “palmitoylated” (chemically modified) in platelets, a process required for activation. In people with SLE (a disease linked to APS), these CMTM proteins are overexpressed—hinting they drive platelet hyperactivity.

3. Innate Immune Cells: The First Line of Defense

Innate immune cells (neutrophils and dendritic cells/DCs) are the body’s rapid response team. In APS, they’re overactivated by aPLs, leading to inflammation and clotting.

Neutrophils: These cells release neutrophil extracellular traps (NETs)—web-like structures that trap pathogens but also promote clots. The review found:
- CKLF1: Attracts neutrophils to inflamed areas and activates them via the MAPK pathway (another pro-inflammatory signal). Anti-CKLF1 antibodies reduce neutrophil infiltration in mouse models.
- CMTM2/6: Overexpressed in neutrophils from APS patients—likely fueling NET release and thrombosis.
Dendritic Cells (DCs): The “conductors” of the immune system, DCs present antigens to T-cells and drive aPL production. CKLF1 is highly expressed in immature DCs and drops as they mature—suggesting it controls how DCs activate T-cells. CMTM3 binds to BLNK (a B-cell signaling protein) in DCs, linking DC activity to B-cell antibody production.

4. Adaptive Immune Cells: T-Cells and B-Cells

Adaptive immunity (T-cells and B-cells) is responsible for long-term immune memory—and in APS, it drives persistent aPL production.

T-Cells: Anti-β2GPI antibodies (the most harmful aPLs) are T-cell-dependent. CKLF1 is a ligand for CCR4 (a receptor on T-cells), helping T-cells home to inflamed tissues. It’s also overexpressed in “germinal center T-cells”—the cells that help B-cells make high-affinity antibodies.
B-Cells: B-cells make aPLs, and their survival depends on signals from proteins like BLNK. The review found:
- CMTM3: Binds to BLNK and enhances ERK signaling (a B-cell activation pathway), promoting antibody production.
- CMTM7: Critical for “B-1a cells”—a subset of B-cells that make natural IgM antibodies. In APS, increased B-1a cells correlate with IgM aPLs. CMTM7 deficiency stops B-1a cell development, reducing aPLs and inflammation.

Why This Matters for APS Patients

APS is tricky to treat—standard therapies (like blood thinners or hydroxychloroquine) target symptoms, not the root cause. The CMTM family offers two exciting possibilities:

Prognostic Markers: Overexpression of CMTM2/6 in neutrophils or CMTM3/5/7 in platelets could predict who with aPLs will develop APS.
Targeted Therapies: Anti-CKLF1 antibodies or CMTM7 modulators could calm inflammation, reduce aPL production, or prevent clots—without the side effects of broad immunosuppressants.

The Road Ahead

While the review highlights strong links between CMTM and APS, most research is preclinical (done in cells or mice). More studies in APS patients are needed to confirm:

Which CMTM proteins are most relevant to human APS.
How CMTM levels correlate with disease severity (e.g., clotting vs. pregnancy complications).
Whether CMTM-targeted drugs are safe and effective.

Still, the findings are promising: the CMTM family connects the dots between aPLs, immune cells, and clotting—offering a new lens to understand and treat APS.

For more details, read the original review: Ge YY, Duan HJ, Deng XL. Possible effects of chemokine-like factor-like MARVEL transmembrane domain-containing family on antiphospholipid syndrome. Chin Med J 2021;134:1661–1668. doi:10.1097/CM9.0000000000001449

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