One model of autoimmunity in which the role of IFN-γ has been studied in detail is collagen-induced arthritis (CIA) in the mouse. In this model, an autoimmune arthritis resembling rheumatoid arthritis (RA) is induced by immunization of genetically susceptible strains of mice with type II collagen [12
]. Disease susceptibility is restricted by the murine class II molecule I-A (specifically I-Ar
], and subsequently, CD4+
T cells play a central role in the immunopathogenesis of this experimental autoimmune disease. The collagen type II (CII)-specific T-cell response is predominated by Th1 cells producing IL-2 and IFN-γ that in turn drive the production of complement-fixing CII-specific IgG2a, a major component in the pathogenesis of this experimental disease [14
Early attempts to define the role of IFN-γ in CIA by the administration of IFN-γ or neutralizing antibodies specific for IFN-γ yielded conflicting results [15
], probably because of variations in timing, sites and means of administration. Studies of CIA development in genetically susceptible mice in which IFN-γ (Y Guedez and E Rosloniec, unpublished observations) or the IFN-γ receptor (IFN-γR) [6
] had been deleted revealed that autoimmune arthritis develops faster and is more severe in the absence of an IFN-γ response. Despite efforts by numerous investigators, a clear consensus on how the absence of a potent Th1 cytokine such as IFN-γ renders an animal more susceptible to a Th1-mediated autoimmune response is still lacking. Although it might be predicted that, in the absence of IFN-γ, there would be a compensatory increase in Th2 cytokines, such as IL-4 and IL-10, no evidence for enhanced expression of any of the Th2 cytokines in these models has been demonstrated. Thus, despite the association of CIA with a strong Th1 response, the absence of an IFN-γ response in genetically susceptible mice enhances the development of autoimmune arthritis, and this occurs despite the lack of CII-specific IgG2a that has been presumed to be a major factor in the initiation of the pathogenesis.
Analogous to the paradoxical role of IFN-γ in CIA is the apparent surprising role of its counterpart, IL-4. When the function of IL-4 was neutralized either by antibody administration or genetic deletion, the onset and severity of CIA were greatly reduced [20
]. Similar results were obtained in a complementary approach using DBA/1 mice expressing an IL-2Rb/IL-4R chimeric transgene. In this approach, IL-2 binding of the receptor transmits a signal via the IL-4 pathway [21
]. Like the IFN-γ-deficient mice, arthritis developed in these chimeric transgenic mice at an accelerated rate and with increased severity. The autoimmune disease was associated with an increase in type 2 cytokines (IL-4, IL-5, IL-10), and an increase in CII-specific IgG1 levels, with IgG2a levels comparable to those in nontransgenic mice. Despite the elevated levels of Th2 cytokines, however, IFN-γ production was not significantly affected, again indicating the complex relationships among these mediators.
A regulatory role of IFN-γ in models of autoimmune arthritis is also supported by studies using strains genetically non-susceptible to CIA. Although CIA susceptibility is restricted to strains expressing H-2q
class II alleles, other strains, such as C57BL/6 (B6, H-2b
), develop marginal T-cell and B-cell immune responses to CII without developing autoimmune arthritis [8
]. Yet when IFN-γ is genetically deleted from the B6 genome (B6 IFN-γ-/-
), these mice become acutely susceptible to the development of CIA [8
]. The arthritis in the B6 IFN-γ-/-
mice is accompanied by an enhanced T-cell response and high amounts of IgG1 and IgG2b CII-specific antibody. Like the studies in the CIA susceptible models, cytokine analysis did not reveal any significant changes in the remaining Th1 or Th2 cytokines but did reveal elevated levels of IL-1β in the lymph nodes and synovial cells of arthritic B6 IFN-γ-/-
mice. The elevated levels of IL-1β appear to be important for the development of the disease, as treatment of B6 IFN-γ-/-
mice with anti-IL-1β significantly reduced the incidence and the severity of the arthritis [8
]. In all, these data serve as a clear example of the complexity of both the dynamics of the cytokine milieu as well as the complex relationships that exist between the Th1 and Th2 cytokines regulating the development of an autoimmune and inflammatory response.