Generally, in autoimmune diseases the inflammatory process is initiated after the presumed autoantigen is presented to lymphocytes by macrophages that act as antigen-presenting cells (APCs). For full activation/immunization, the lymphocyte has to receive two signals: (1) one provided by the MHC-antigen complex, which binds to the specific TCR (T-cell receptor); and the second (2) supplied by the B7-CD28 (adhesion molecule) complex. In the absence of the secondary costimulatory signal, the lymphocytes fail to produce the T-cell growth factor interleukin-2 (IL-2) and, therefore, antigen presentation leads to anergy of the lymphocytes towards the specific antigen.1 There are also other accessory molecules, like the LFA1/ICAM-1, the CD40/CD40L (ligand) and the LFA3/CD2 complexes, which enhance lymphocyte reactivity in a non-specific manner. The latter represent a second pathway (independent of the TCR pathway) for T-cell activation.
Following activation by macrophages/APCs, lymphocytes (mainly of the helper CD4 subtype) expressing the specific TCR proliferate and expand. In parallel, they begin to express on their cell surface adhesion molecules/markers of activation (LFA1,3, ICAM-1, VLA-4) which help them to invade the vessel endothelium at the site of inflammation.2-4 T-helper cells differentiate, becoming either Th1 cells, which stimulate cytotoxic, or CD4 T-cells (positive feedback) by producing IL-2, IL-12, TNF-a and IFN-7 (pro-inflammatory cytokines), or Th2 cells, that help mainly B-cells (producing auto-antibodies) and secrete IL-4, IL-6 and IL-10.5-7 There is a 'balance' between the Th1 and Th2 subpopulations; in T-cell-mediated autoimmune diseases like multiple sclerosis (MS), the lymphocytes involved in the inflammatory process are mainly of the Th1 pheno-type. However, the acquisition of a specific pheno-type (Th1 or Th2) is rather transient, and the status of lymphocytes can be changed according to the immunologic milieu. It seems, therefore, that there are no 'good' and 'bad' cells, but the same cell can be differentiated in both directions. We believe that the Th1 to Th2 shift is a transient event and is not universally helpful in autoimmunity. Actually, such a shift may be harmful in antibody-mediated autoimmunity, as was recently shown in MOG (membrane oligodendrocyte glycoprotein)-induced EAE,8 whereas it may be helpful in T-cell-mediated autoimmune diseases, like MS, but such a shift should not be permanent and it may be associated with increased danger for induction of antibody-mediated autoimmunity.
CD4 lymphocytes are also functionally and phenotypically divided into two subpopulations. The first population comprises 'memory' cells, which, after the initial encounter with the antigen, are rapidly induced to react/proliferate following a second exposure. These cells express the CD45 RO surface marker on their membranes. The second subpopulation is of the CD45 RA phenotype, and consists of cells which function as 'suppressor-
inducers'.5-9 There is probably a cyclic relationship between CD4+ subpopulations: naive CD45Ra+ cells convert to CD45Ro+ memory cells upon antigen stimulation, but without continuous antigen stimulation they lose their CD45Ro expression and revert to being long-lived CD45Ra+ cells.10-11 These CD45Ro+ lymphocytes represent activated memory cells and they are probably identical to the CD29+ lymphocytes expressing on their surface the b-chain of the VLA antigens (b1 integrins),12 which is upreg-ulated to facilitate adhesion to endothelial cells and subsequent passage into sites of inflammation. In MS and in other autoimmune diseases, like rheumatoid arthritis, autoimmune hemolytic anemia, Guillain-Barre Syndrome (GBS) and systemic lupus erythe-matosous (SLE),13-18 the CD45Ra+ cells are usually downregulated, especially during the active phases (relapses) of the disease. In a longitudinal study, it was shown that newly diagnosed cases with SLE initially have a higher proportion of CD45Ra+ cells, which, as the disease progresses, reduces as a shift towards the CD45Ro phenotype takes place. This shift seems to be the result of conversion of resting cells into activated memory lymphocytes. However, since the CD45Ra+ cells are found in lower numbers in patients with autoimmune diseases as compared to age-matched healthy individuals, this finding may also indicate that loss of suppressor function could be, at least partially, related to the immunopathogenesis of autoimmunity in general; a low proportion of suppressor-inducer cells could permit autoreactive clones to carry out an autoimmune attack.
The basic concepts for self/non-self-discrimination and autoimmunity seem to be in a process of revision. Actually, it has been shown that even naive neonatal thymocytes can proliferate and react to any antigenic stimulation, depending on the 'conditions' provided. The potential for autoimmunity may exist in almost any individual with the suitable genetic background. What prevents autoimmunity is an immune network fully equipped with several immunoregulatory populations which—when they function properly—do not allow the outburst of autoreactivity. In support of this theory, several studies have reported immunologic defects observed in patients with neuroimmunologic diseases, thus indicating that malfunction of immunoregulatory mechanisms may be involved in the pathogenesis of these diseases. The most documented include defective suppressor cell activity, reduced NK cell activity and reduced proportions of suppressor-inducer cells,13-15,18-20 all of which correlate reciprocally (negatively) with disease activity.
Genetic background (multiple genes)
Genetic background (multiple genes)
Thus, for autoimmunity to develop, several events have to take place in a complicated interplay: (1) there has to be a specific (autoimmune-prone) genetic background (specific HLA subtypes); (2) there must be a 'trigger', usually an infectious agent; and (3) a dysregulation of the immune system has to occur, namely a defect in the normally existing suppressor/downregulatory immune mechanisms mentioned above. A schematic representation of this interplay between the components of this setting in autoimmune diseases is shown in Figure 1.1.
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