Paper # 096 Versiˇn en Espa˝ol Spanish version

Thymic microenvironmental changes in human congenital syphilis

Eliene C. Fonseca, M˘nica P. Almeida, ╔vlin H. Maia, Dora M. F. Menezes and Wilson Savino*

[Title] [Materials and Methods] [Results] [Discussion] [Pictures] [Bibliography]

Title

Materials & Methods

INTRODUCTION

 

The thymus is an organ in which death and differentiation are physiological processes related to the establishment of the so-called T cell repertoire. Thymus weight and cellularity varies throughout pre and post human natal development, reaching higher values in puberty, when it begins a gradual and physiological involution, called "natural involution". A thymic rudiment can be identified in the fourth week of embriogenesis from proliferation of ectodermal cells of thrird branchial cleft and mesodermal cells of the third pharyngeal pouch. Pre-thymic lymphocytes from fetal liver and bone marrow begin to colonize it and interact with this embrionary tissue that will form lymphoid and microenvironment thymic components. Along with these processes. lymphocytes undergo paramount influences from the thymic microenvironroent, via polypeptide secretion as hormones and interleukins and membrane interactions as those involving MHC products and adhesion molecules, both expressed on thymic epithelial cells, macrophages and interdigitating cells (1, 2, 7, 14, 27, 33, 39, 40) and extracellular matrix (6, 13, 14, 16, 20, 24, 34, 36, 43, 44), altering the expression of several membrane antigens - as CD3, CD4, CD8, TCR molecules (2, 3, 7).

The presence of extracellular matrix (ECM) components in the thymus (8, 13, 16, 17, 18, 24, 36, 37, 44), together with the detection of fibronectin receptors in cortical thymocytes (41, 43) associated to the previous knowledge on the importance af ECM molecules in cell migration. proliferation and differentiation in other biological systems yielded the hypothesis that ECM proteins might play a role in intra-thymic events of T cell differentiation. Taking into account a number of data obtained in our laboratory (6, 11, 12, 16, 17, 18, 21, 23, 29, 31, 34, 35, 36, 43, 44) suggesting a role for ECM in thymocyte death and proliferation in experimental animal models, we decided to investigate a putative correlation between the degree of thymocyte death and the amounts of intra-thymic ECM (assessed by histological and immunohistochemical techniques) in thymuses from children undergoing intrauterine disorders as congenital syphilis.

Congenital syphilis (CS) results from infection of the fetus with Treponema pallidum before birth. Characteristicaly, the infants shows retardation of development in all the viscera, and the fatal forms of CS exhibits widespread fibrosis and plasma cells infiltration (15). Perivascular localization of this bacteria appears to be related to the findings of collgen rings around arterioles (10, 11), simulating the "onion skin" vascular pattern of lupus erytematosus. This fact is probably related to RGD peptides (Arginine-Glycine-Aspartic acid) sequence, that is commom to proteins with adhesive function, including integrins ligants on ECM molecules as fibronectin, laminin and collagens (36), as well as pathogens receptors associated with host-parasite relationship like Treponema pallidum surface molecules (25).

Humoral immune response to Treponema pallidum infection shows polyclonal B cell activation and immunecomplexes containing autoantibodies to fibronectin, fibronectin degradation products and fibronectin ligants (4, 5). T cell response seems to be important in experimental infections whereas thymic and white pulp lymphocyte depletion are observed in congenital human disease.

Actually lymphocyte depletion parallel to increase in ECM- containing network were common findings positively correlated. Additionally to uncommon pattern of abnormal intra-thymic ECM distribution we observed anti-ECM B cell autorreactivity, evidenced by circulanting anti-ECM antibodies as well as intrathymic immunoglobulin bound to ECM structure, particularly basement membrane.

Our results clearly show that in human congenital syphilis as well as in citomegalovirus and measles infections (umpublished data) and Down’s syndrome(13), there a close relationship between the degree of thymic atrophy and the increase in intralobular extracellular matrir contents. independently of the disorder under study. Considering that such ECM abnormalities occur in fetal or neonatal life. it is possible that they may somewhat modify the normal pattern of the T cell repertoire.


Title

Materials & Methods