Delineating the genetic basis of systemic lupus erythematosus.

Role of natural and immune IgM antibodies in immune responses.

Complement has both beneficial and deleterious roles in the pathogenesis of systemic lupus erythematosus (SLE). On the one hand, patients with SLE present with decreased complement levels and with complement deposition in inflamed tissues, suggestive of a harmful role of complement in the effector phase of disease. On the other hand, homozygous deficiency of any of the classical pathway proteins is strongly associated with the development of SLE. There are two main hypotheses to explain these observations. The first invokes an important role for complement in the physiological waste-disposal mechanisms of dying cells and immune complexes. The second hypothesis is based around the role of complement in determining the activation thresholds of B and T lymphocytes, with the proposal that complement deficiency causes incomplete maintenance of peripheral tolerance. These two hypotheses are not mutually exclusive. In addition, there is evidence for a contribution from other genetic factors in determining the phenotype of disease in the absence of complement.

The Role of Complement in the Development of Systemic Lupus Erythematosus

http://www.epivax.com/wp-content/uploads/2013/09/De_Groot_Scott_Trends_final.pdf

Immunogenicity of protein therapeutics

FcγRIIB is the only inhibitory Fc receptor for IgG, common genetic variants of which are associated with susceptibility to autoimmune disease but, also, with protection from severe malaria. Furthermore, understanding the function of FcγRIIB has important implications for the use of therapeutic antibodies.

/pdf/fcgriib-in-autoimmunity-and-infection-evolutionary-and-3id7qvmw6d.pdf

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications

Cr2-/- mice have an impairment in humoral immunity, as shown by the decrease in the Ab titers against T cell-dependent Ags and abnormalities in germinal center formation. Germinal centers are present, but they are decreased in size and number, indicating problems in their development. In this study, we investigated whether this abnormality in germinal center development is associated with problems in the establishment of optimal affinity maturation and the generation of memory B cells, processes closely related to the germinal center reaction. We immunized the Cr2-/- animals with different Ags with or without adjuvants. We showed that, when immunized without adjuvants, complement receptors are absolutely required for optimal affinity maturation. Although limited affinity maturation is elicited in the Cr2-/- Ab response, it is decreased as compared with normal animals. Memory B cell generation is also impaired. In the presence of adjuvants, germinal center development in the Cr2-/- mice is still abnormal, as demonstrated by their decreased size and number. Surprisingly, adjuvants establish optimal affinity maturation and partially restore the amount of Ab produced during the primary response and memory B cell generation. However, adjuvants cannot improve the ability of follicular dendritic cells to retain Ags in the form of immune complexes. These observations indicate that immunization with inflammatory Ags offset some of the immunological abnormalities found in the Cr2-/- mice and show that optimal affinity maturation in the Cr2-/- mice can be achieved in the absence of normal germinal centers.

Impaired affinity maturation in Cr2-/- mice is rescued by adjuvants without improvement in germinal center development.

Systemic lupus erythematosus is an autoimmune disease characterized by autoantibody production against nuclear Ags. Recent studies suggest that the Cr2 gene, which encodes for complement receptor (CR)1 and CR2, is important in disease susceptibility. Because the precise disease phenotype related to this gene, in isolation or in relation to other genetic loci, is not known, we analyzed C57BL/6 mice with a targeted mutation in Cr2 (C57BL/6. Cr2 −/− ) with or without a concomitant mutation in Fas (C57BL/6 .lpr Cr2 −/− ). The Cr2 null mutation in a C57BL/6. lpr background markedly increases the serum concentrations of IgG1 and IgG2b and the levels of antinuclear and anti-dsDNA Abs as compared with C57BL/6. lpr controls. There is also a trend for higher concentrations of IgG2a and IgG3. In contrast, isolated deficiencies in either these CRs or Fas have a limited effect in the production of anti-dsDNA Abs. Moreover, the Cr2 null mutation does not affect other disease manifestations. These findings demonstrate that abnormalities in CR1 and CR2 may be linked to the production of autoantibodies by modifying the effect of other systemic lupus erythematosus susceptibility genes. Phenotypic expression of other disease manifestations need additional Cr2 -independent genetic factors.

A Role for the Cr2 Gene in Modifying Autoantibody Production in Systemic Lupus Erythematosus

D. MolinaGregory Dolecki, Dailing Mao, Laurence Morel and Hector Xiaobo Wu, Ning Jiang, Christine Deppong, Jasvinder Singh,http://www.jimmunol.org/content/169/3/1587J Immunol€2002; 169:1587-1592; ;Referenceshttp://www.jimmunol.org/content/169/3/1587.full#ref-list-1This article cites 36 articles, 20 of which you can access for free at: Subscriptionshttp://jimmunol.org/subscriptionsInformation about subscribing to The Journal of Immunology is online at: Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at: Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:

Autoantibody Production in Systemic Lupus A Role for the Cr2 Gene in Modifying

Antibody production in mice deficient for complement receptors 1 and 2 canbe induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes.

Antibody Production in Mice Deficient for Complement Receptors 1 and 2 Can Be Induced by IgG/Ag and IgE/Ag, But Not IgM/Ag Complexes

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Impaired affinity maturation in Cr2-/- mice is rescued by adjuvants without improvement in germinal center development.

A Role for the Cr2 Gene in Modifying Autoantibody Production in Systemic Lupus Erythematosus

Autoantibody Production in Systemic Lupus A Role for the Cr2 Gene in Modifying

Antibody Production in Mice Deficient for Complement Receptors 1 and 2 Can Be Induced by IgG/Ag and IgE/Ag, But Not IgM/Ag Complexes