T Cell Regulation and MHC Restriction

As summarized in Section 1, EAT susceptibility and resistance are categorized by their MHC class II gene differences. Since susceptible mice have naturally existing CD4+CD25+ T cells (Morris and Kong, 2004), it was of interest to determine if CD4+CD25+ T cells also influence EAT induction in resistant strains. In pilot experiments using two EAT-resistant strains, prior depletion of CD4+CD25+ T cells in both BALB c (H2d) mice (Wei et al, 2004) and B10 (H2b) mice (Morris et al., 2004) enabled the...

Innate Immunity in Experimental Autoimmune Myocarditis

A century has passed since the epic publication by Donath and Landsteiner (1904) on the pathogenesis of paroxysmal cold hemoglobunaria (PCH). The work provided the first hint that autoimmunity could be the cause of human disease. The concept remained fallow for half a century until improved immunologic methods and a broader view of the basis of the immune response validated the idea. Landsteiner associated PCH with his concurrent studies of syphilis, leading to the suggestion that infection may...

Human Autoimmunity An Abnormality of B Cell Function

The original concept of autoimmunity was based on the presence of antibodies to self B cell autoreactivity (Landsteiner, 1904). One hundred years later, there is a broad body of evidence for abnormalities of B cell function in a wide Jonathan C. W. Edwards, Geraldine Cambridge, and Maria J. Leandro University College London Centre for Rheumatology, Arthur Stanley House, London W1T 4NJ, England. Molecular Autoimmunity In commemoration of the 100th anniversary of the first description of human...

Factors Involved in Treg Induction

The mechanism by which regulatory T cells are induced will likely have an impact on the phenotype of these cells. Regulatory T cells are thought to be primed by antigen-presenting dendritic cells (DCs). Recent evidence has suggested that many subsets of DCs exist that vary in their surface molecule expression, cytokine production, as well as the class of T cell response they are capable of inducing (Moser and Murphy, 2000). Thus, one factor that may influence the outcome of therapeutic...

Do Data from BLyD Support the Trojan Horse Concept

The use of BLyD has, therefore, provided us with a powerful new tool with which to treat a number of autoimmune conditions and, perhaps more importantly for the future, to probe underlying pathogenic mechanisms. It was initially thought by some that BLyD would not work in such autoantibody-associated conditions, since rituximab-based ablation of circulating B cells in lymphoma for a period of many months was not associated with major falls in immunoglobulin levels (McLaughlin, 2001 Grillo-Lopez...

Mechanisms of Estrogen Effects on the Immune System

Estrogen Exerts Its Biological Effects on Cells by Both Estrogen Receptor-Dependent and -Independent Mechanisms A concise description of ERs and their interactions with DNA is helpful to appreciate the molecular mode of action of estrogens and to understand the diversity of potential effects of estrogens on the immune system. Estrogen exerts its biological functions on target tissues by both ER-dependent and ER-independent mechanisms. Estrogen binds to two specific, but distinct receptors,...

Reactive Protein as a Regulator of Autoimmune Disease

Reactive Protein Synthesis

C-reactive protein (CRP) is a phylogenetically ancient, highly conserved component of the innate immune system. The pentraxin family, which includes CRP and serum amyloid P (SAP) component, is represented in all vertebrate species studied as well as in several invertebrates. Throughout evolution, pentraxins have retained similar amino acid sequence, structure, and calcium-dependent ligand-binding sites. CRP was identified and named for its ability to precipitate the C-polysaccharide of...

Defective Clearance of Self Antigens in SLE

Aberrant rates of apoptosis and increased levels of free-circulating chromatin have been reported in human lupus (Amoura et al., 1997), and humans with DNASE1 and C1q gene mutations develop SLE (Kirschfink et al., 1993 Yasutomo et al., 2001), suggesting that efficient removal of chromatin or chromatin-protein complex is crucial to prevent SLE. For example, serum amyloid P component (SAP)-deficient mice develop an SLE-like syndrome (Bickerstaff et al., 1999). Two models are likely to explain the...

Naturally Existing CD4CD25 T Cells as Peripheral Barrier to Autoimmune Thyroiditis

As we have hypothesized earlier and discussed above, there is a clonal balance of regulatory T cells and autoreactive T cells, with the former keeping the latter in check in normal, susceptible individuals (Kong et al., 1982). This hypothesis has certainly been borne out by transfer experiments in which CD4+CD25- T cells, transferred without CD4+CD25+ T cells, mediated the development of several autoimmune diseases including thyroiditis (Sakaguchi et al., 1995). The depletion of CD4+CD25+ T...

The Autoimmune Hypothesis of Multiple Sclerosis

MS is one of the most common neurological diseases within developed countries. It usually starts in young adults and leads in a chronic relapsing or progressive course over many years to major neurological disability (Noseworthy et al, 2000). Genetic factors are important in determining the susceptibility to develop this disease, but within families of MS patients no Mendelian pattern of inheritance is found (Kalman and Lublin, 1999). Furthermore, studies on identical twins show that in...

T Cell Signaling Abnormalities in Systemic Autoimmune Disease

The critical contribution of T cells to the generation and perpetuation of systemic autoimmune disease is beyond question. In experimental models they can transfer disease, and genetically engineered antigen-specific autoreactive T cells can promote sustained autoimmunity. In addition, treatment modalities that interfere with T or B cell function ameliorate disease. The discovery by two independent groups (Fields et al., 1996 Li et al., 1996) of the role of the route leading to transcription...

The Critical Role of B Cells in Autoimmunity

The main immunological event in the pathogenesis of SLE is B cell hyperactivity, and several lines of evidence demonstrate that B cells are essential for development of autoimmunity and disease expression (Lu and Cyster, 2002 Zouali, 2005). Transfer of cultured pre-B cells derived from (NZB x NZW) F1 fetal liver into SCID mice is sufficient to generate a lupus-like syndrome (Reininger et al., 1992). Since T cells do not develop from these donor cells, it appears that B-lineage-intrinsic defects...

Antigen Clearance and Autoimmunity

DNASEI-Deficient Patients Gene Mutation and Clinical Features Naiperi et al. (2000) reported that DNASE1-deficient mice develop an SLE-like syndrome even if the DNASE1 mutation is heterozygous (Napirei et al., 2000). Like humans with SLE, these mice possess very high titers of anti-dsDNA antibodies and develop severe glomerulonephritis. When the DNASEl-coding sequence and exon-intron boundaries were scanned for mutations, an A to G transversion in exon 2 at position 172 of the cDNA...

Estrogen and Lupus Human and Animal Studies

It is beyond the scope of this chapter to discuss the role of estrogens in all autoimmune diseases. Therefore, we focus primarily on estrogen effects on lupus, since the effects of this hormone have been noted in humans and in murine models of lupus. SLE patients have autoantibodies against many self-antigens including double-stranded DNA (dsDNA), red blood cells, platelets, leukocytes, and clotting factors, which leads to the formation of immune complexes. The deposi tion of these immune...

Acute Poststreptococcal Glomerulonephritis

Acute poststreptococcal glomerulonephritis (APSGN) is the most common postinfectious renal disease following group A streptococci (GAS) infection, and the first form of glomerular disease in which immunological mechanisms were suspected to play a role. In fact, its evolution is characterized by a serum sickness-like latent period followed by hypocomplementemia and nephritis (Nordstrand et al., 1999). Researchers originally believed that the pathogenic mechanism underlying APSGN was the renal...

Concluding Remarks and Perspectives

Complete deficiencies of C4A and C4B are among the strongest genetic risk factors associated with SLE or lupus-like diseases, across all HLA haplo-types and racial backgrounds. However, the age of disease onset and the disease severity vary substantially among the C4-deficient subjects, which underscores the importance of other genetic and environmental factors contributing to disease pathogenesis and progression. In contrast to the rarity of complete C4A and C4B deficiencies, partial and...

IFNg in SLE and Other Autoimmune Diseases

Several lines of evidence implicate IFNy in inflammatory autoimmune disease (Billiau, 1996 Schwarting et al., 1998). First, signaling through the IFNy receptor is essential for the initiation and progression of lupus nephritis in lupus-prone, MRL-lprfas mice (Schwarting et al., 1998). Second, the IFNy-related transcription factor T-bet has been shown to regulate IgG2a class switching and induction of pathogenic autoantibodies in murine lupus (Peng et al., 2002). Third, during the course of SLE,...

Disrupted B Cell Signaling Pathways in Human Autoimmunity

As discussed above, experimentally induced modification of receptor expression or alteration of signaling pathways may have a significant impact on B cell tolerance to self. In humans too, there are indications that abnormal B cell signaling may contribute to autoimmune disease. In lupus, stimulation of circulating B cells through their sIgM produced significantly higher Ca2+ fluxes compared with similarly induced responses of B cells from patients with other systemic rheumatic diseases...

Deficiencies of C4A or C4B in Human SLE

Low Complement Activity and C4 Protein Concentrations in SLE It has been known for over half a century that SLE patients manifest reduced complement hemolytic activity (CH50) (Vaughan et al., 1951 Elliot and Mathieson, 1953). Reduced serum or plasma levels of complement C1q, C4, and C3 have been consistently observed in lupus patients, particularly those with lupus nephritis (Lewis et al., 1971 Cameron et al., 1976 Hebert et al., 1991). Serial analysis of serologic factors in SLE revealed...