Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA.
Objective
To describe systemic autoimmune joint diseases following Lyme disease and to compare their clinical features with Lyme arthritis.
Methods
Records of all adult patients referred to our Lyme arthritis clinic over a 13-year period in whom we diagnosed a systemic autoimmune joint disease following Lyme disease were reviewed. For comparison, records of patients enrolled in our Lyme arthritis (LA) cohort over the most recent 2-year period were analyzed. IgG antibodies to Borrelia burgdorferi and to 3 Lyme disease-associated autoantigens were measured.
Results
We identified 30 patients who developed a new-onset systemic autoimmune joint disorder a median of 4 months after Lyme disease, usually erythema migrans (EM). Fifteen had rheumatoid arthritis (RA), 13 had psoriatic arthritis (PsA), and 2 had peripheral spondyloarthropathy (SpA). The 30 patients typically had polyarthritis; and those with PsA/SpA often had previous psoriasis, axial involvement, or enthesitis. In the comparison group of 43 LA patients, monoarticular knee arthritis, without prior EM, was the usual clinical picture. Most systemic autoimmune patients had positive tests for B. burgdorferi IgG antibodies by ELISA, but they had significantly lower titers and lower frequencies of Lyme-associated autoantibodies than LA patients. Prior to our evaluation, the patients often received additional antibiotics for presumed Lyme arthritis without benefit. We prescribed anti-inflammatory therapies, most commonly disease modifying anti-rheumatic drugs (DMARDs), resulting in improvement.
Conclusion
Systemic autoimmune joint diseases, RA, PsA/SpA, may follow Lyme disease. Development of polyarthritis after antibiotic-treated erythema migrans, previous psoriasis, or low-titer B. burgdorferi antibodies are clues to the correct diagnosis.
Our findings indicate that the subclasses of IgG antibodies to B burgdorferi differ from those of LD-associated autoantibodies. Furthermore, the correlation of IgG4 autoantibodies with specific synovial pathology in the refractory group suggests a role for these autoantibodies, either protective or pathologic, in antibiotic-refractory Lyme arthritis.
BACKGROUND:
Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown.
METHODS:
We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled WT versus
Myd88
−/−
mouse T cells at the transcript and protein level and performed several functional assays.
RESULTS:
Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated
Myd88
−/−
T cells had increased proinflammatory signaling at the transcript and protein level compared with WT, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling.
CONCLUSIONS:
Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.