Connective Tissue Diseases & the Immune System

Connective tissue diseases such as Ehlers-Danlos Syndrome (EDS) and Marfan Syndrome (MFS) are overlapping conditions that are often linked with mutations in connective tissue genes, such as collagen (implicated in EDS) and fibrillin (implicated in MFS). One of the main functions of these proteins is to form the basis of the extracellular matrix that surrounds most cells of the body and gives tissues their structure, strength, and elasticity.

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Interestingly, some individuals with EDS present with a Marfanoid (Marfan-like) habitus, a constellation of symptoms including long limbs, crowded teeth, a high-arched palate, and long fingers. Still others with EDS may not have a full Marfanoid habitus but present with minor features, such as rib cage deformities like pectus excavatum and pectus carinatum. This overlap suggests that EDS and MFS may have more in common than hypermobility.

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EDS and MFS also share high rates of immune dysregulation, frequently presenting with respiratory and food allergies, rhinitis, asthma, eczema, and GI distress [1, 2]. Some of my team’s current work is focused on these issues in EDS and autism, which I hope to blog about in coming months.

Frischmeyer-Guerrerio et al. (2013) have found that in MFS and a closely-related condition known as Loeys-Dietz Syndrome, dysregulation of the TGF-beta pathway is key in regulating immune system activation, potentially leading to the associated symptoms mentioned above. In fact, a minority of cases of MFS are associated with TGFBR2 mutations, a gene that codes for one of the TGF-beta receptor subunits [3].

Interestingly, TGF-beta is normally sequestered by the extracellular matrix and kept “in waiting,” ready to be released when needed. It raises the question whether a faulty extracellular network is incapable of performing this function properly, leading to premature release of TGF-beta, triggering downstream immune signaling and perhaps even leading to inflammation within local tissues [4]. It also raises the possibility that TGF-beta signaling somehow affects the development and maintenance of the extracellular network.

While TGF-beta hasn’t been studied in EDS in general, scientists have found that TGF-beta blood levels are high in people with Vascular EDS, a very severe and sometimes deadly form of the condition [5]. Although numbers are currently low, our preliminary work suggests that people with Vascular EDS report similar rates of immune symptoms as the Hypermobile and Classic forms of EDS, suggesting TGF-beta levels could be upregulated in these other forms as well.

TGF-beta not only interacts with the extracellular network and the immune system, it is also a powerful morphogen during early development, helping to determine structure and function of tissues in the body. Therefore it sits at a perfect crossroads.

 

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