Genetic Differences in Bone Marrow-Derived Lymphoid Lineages Control Susceptibility to Experimental Autoimmune Myocarditis

Abstract

Bone marrow (BM) transplantation has been used to study the cellular basis of genetic control of autoimmune diseases, but conclusions remain elusive due to the contradictory findings in different animal models. In the current study, we found that BM cells from myocarditis-susceptible A.SW mice can render irradiated, myocarditis-resistant B10.S recipient mice susceptible to myosin-induced myocarditis, indicating that hematopoietic cells express the genetic differences controlling susceptibility to autoimmune myocarditis. We then sought to differentiate the role of lymphoid vs nonlymphoid components of BM in the pathogenesis of myocarditis by comparing mixed chimeras receiving BM from A.SW wild-type or RAG−/− mice mixed with BM from B10.S wild-type mice. This experiment clearly demonstrated that T and B lymphocytes were indispensable for transferring the susceptible phenotype to disease-resistant recipients. Our findings significantly narrow the cellular expression of genetic polymorphisms controlling the EAM phenotype.

Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4+ T cells

“…We have extended here our previous findings showing that genetic susceptibility to EAM was mediated by T lymphocytes [17]. We showed that intrinsic differences in the frequency of CD4 + T cells and Tregs and their ability to receive cytokine instruction to differentiate towards specific T helper subtypes could represent a factor in the susceptibility of A.SW and B10.S mice to autoimmune myocarditis.…”

“…Using bone marrow chimeric mice, we have shown previously that genetic susceptibility of myocarditis is controlled by donor‐derived haematopoietic cells, and that T and B lymphocytes were indispensable for transferring the susceptible phenotype to disease‐resistant recipients [17]. To continue with this line of research, we performed a comprehensive flow cytometric analysis of splenocytes from naive A.SW and B10.S mice.…”

“…Myocarditis severity was evaluated at the peak of disease on day 21. Hearts were cut and stained with haematoxylin and eosin (H&E), according to standard protocol (Histoserv, Inc., Germantown, MD, USA) [17]. The degree of EAM was scored based on the percentage of the area of leucocyte‐infiltrated myocardium, as follows: grade 0 = no infiltration, grade 1 = < 10%, grade 2 = 10–30%, grade 3 = 30–50%, grade 4 = 50–90% and grade 5 ≥ 90% [2].…”

Myocarditis in Humans and in Experimental Animal Models

“…α-MyHC/CFA immunization induces myocarditis in susceptible strains only. Mice on BALB/c, A/J or A.SW background are susceptible to EAM, while mice on C57BL/6 background are resistant (134, 159–161). From a practical point of view, the resistance to EAM of widely-used C57BL/6 strain limits use of numerous transgenic models without the need for back-crossing onto the susceptible background.…”

Decreased expression of Fli-1 in bone marrow-derived haematopoietic cells significantly affects disease development in Murphy Roths Large/lymphoproliferation (MRL/lpr) mice

“…Bone marrow (BM) transplantation is used to investigate the contribution of haematopoietic versus non‐haematopoietic cell lineages in autoimmune disease development [14,15]. In this study, our aim was to investigate whether BM‐derived cells play a role in the profound improvement of renal disease and survival in Fli‐1 +/− MRL/ lpr mice.…”