Does HTLV-1 Infection Show Phenotypes Found in Sjögren's Syndrome?

Abstract

Viruses are a possible cause for Sjögren's syndrome (SS) as an environmental factor related to SS onset, which exhibits exocrine gland dysfunction and the emergence of autoantibodies. Although retroviruses may exhibit lymphocytic infiltration into exocrine glands, human T-cell leukemia virus type 1 (HTLV-1) has been postulated to be a causative agent for SS. Transgenic mice with HTLV-1 genes showed sialadenitis resembling SS, but their phenotypic symptoms differed based on the adopted region of HTLV-1 genes. The dominance of tax gene differed in labial salivary glands (LSGs) of SS patients with HTLV 1-associated myelopathy (HAM) and adult T-cell leukemia. Although HTLV-1 was transmitted to salivary gland epithelial cells (SGECs) by a biofilm-like structure, no viral synapse formation was observed. After infection to SGECs derived from SS patients, adhesion molecules and migration factors were time-dependently released from infected SGECs. The frequency of the appearance of autoantibodies including anti-Ro/SS-A, La/SS-B antibodies in SS patients complicated with HAM is unknown; the observation of less frequent ectopic germinal center formation in HTLV-1-seropositive SS patients was a breakthrough. In addition, HTLV-1 infected cells inhibited B-lymphocyte activating factor or C-X-C motif chemokine 13 through direct contact with established follicular dendritic cell-like cells. These findings show that HTLV-1 is directly involved in the pathogenesis of SS.

Keywords: HTLV-1; Sjögren’s syndrome; follicular dendritic cell; salivary gland epithelial cell; viral infection.

Figure 1

Development of HTLV-1 gene transgenic animals. Four types of HTLV-1 Tg rodents have been created to date. Sialadenitis was observed in tax Tg mice, and Tax protein expression was confirmed in salivary glands and muscle tissue by immunoblotting. Arthritis similar to rheumatoid arthritis was observed in env-pX mice, and an increase in inflammatory cytokines in synovial fluid was observed. In env-pX rats, inflammation was observed in salivary glands, muscles, and joint tissues. In HBZ Tg mice, Foxp3-positive T cells were increased, and skin and lung inflammation were confirmed. HBZ: HTLV-1 bZIP factor, IL: interleukin, Tg: transgenic, TNF: tumor necrosis factor.

Figure 2

Hypothetical scheme of the transmission of HTLV-1 virions. There are at least three known methods.for transferring viral particles from HTLV-1-infected lymphocytes to non-infected lymphocytes: the biofilm theory, the viral synaptic theory with microtubule organizing center (MTOC) formation, and the cellular conduits theory mediated by the HTLV-1 p8 molecule. It was also suggested that biofilms such as tetherin and agrin are involved in the transfer of virus particles from infected lymphocytes to salivary gland epithelial cells (SGECs). There is also the possibility of transmission via cellular conduits, but it may differ from the transmission between lymphocytes, such as lack of lymphocyte function-associated antigen 1 (LFA-1) accumulation.

Figure 3

Involvement of HTLV-1 infected SGECs in SS. Virus particles are exposed on the surface of HTLV-1-.infected cell lines, and these infected cell lines produce molecules involved in adhesion, inflammation, and migration, such as ICAM-1, IP-10, and RANTES. HTLV-1 particles migrate to the salivary glands via cell-to-cell contact with infected cells and HTLV-1 DNA becomes integrated into some SGECs. The infected SGECs themselves also have the ability to produce ICAM-1, IP-10, and RANTES, and can be involved in chronic inflammation.

Figure 4

Hypothesis regarding the inhibitory effect of HTLV-1 against autoantibody production system in SS. B cells receive signals from follicular helper T cells (Tfh) after contact with follicular dendritic cells (FDCs) present in the germinal center outer layer. In cooperation with Tfh, memory B-cell production or plasma cell maturation and autoantibody production such as anti-Ro/SS-A antibody occur. Among the autoantibody production pathways, FDC plays a central role in B-cell homing by CXCL13 and B-cell activation and differentiation by BAFF (B-cell activating factor belonging to the tumor necrosis factor family). HTLV-1-infected cells may act directly on FDCs and reduce FDC function by suppressing the production of CXCL13 and BAFF.