Cure Arthritis Naturally

Cure Arthritis Naturally

Get Instant Access


Proteoglycan (aggrecan)

Further, passive transfer of transient arthritis is seen with the transfer of sera from arthritic mice or rats to naive animals. More profound is the ability of sera from a human with polyarthritis to induce arthritis similar to CIA in mice. As with the passive transfer of murine antibodies against CII, this arthritis is also transient in nature. This is in sharp contrast to CIA where chronic arthritis develops, culminating in joint destruction. Thus, autoantibodies do play a role in the pathogenesis of CIA, but their specific role in disease induction is yet to be clarified.

Cellular responses to CII are also involved in the pathogenesis of CIA. T cells and specific T cell receptors are clearly involved in the initiation of CIA. Mice with genomic deletion of specific T cell receptors have been shown to be resistant to the induction of CIA (see later). Furthermore, treatment of mice with anti-T cell agents prevents CIA and athymic nude mice are resistant to CIA.

Immunogenetic regulation of CIA

The immunogenetic control of CIA in mice has been extensively studied, providing considerable knowledge regarding the predisposition to CIA in mice and other models. Susceptibility to CIA in mice has been shown to be dependent on the presence of a trimolec-ular complex including: 1) a susceptible MHC haplo-type, 2) the presence of self-reactive T cells utilizing selected T cell receptor (TCR) Vp chains, and 3) arthritogenic epitopes on the collagen molecule. MHC genes have been mapped to the H-2A locus, using inbred, congenic and recombinant mouse strains. Mouse strains expressing the MHC haplo-types H-2q and H-2r are susceptible, while other haplotypes of mice are resistant to the induction of CIA. In addition, studies utilizing CIA-resistant B10.P (H-2P) and CIA-susceptible DBA/1, B10.G (H-2q) strains of mice have localized a critical restriction site on the H-2A (3 chain that is important in CIA susceptibility.

Comparison between sequences in the A(3 first domain of H-2" and H-2P genes has revealed amino acid differences at positions 85-89 which are critical in CIA susceptibility. This region of the A(3 molecule is suggested to be localized at the end of an a helix, important for interaction between the TCR, the MHC molecule and an antigenic peptide. This 85-89 amino acid stretch has been further analyzed in CIA susceptibility. H-2P mice transgenic for an App gene mutated to resemble the Aj3q develop CIA, supporting the role of the A(3 gene in predisposition to CIA. While considerable progress has been made in identifying a critical role of the H-2A molecules in CIA susceptibility, recent work from our laboratory has demonstrated a protective role for the H-2E mol ecules in CIA. Experiments were performed using a recombinant mouse strain (B10.RQB3), which possesses functional H-2A'' and Eak molecules, but lacks an intact H-2E molecule due to a nonfunctional E0 gene. However, B10.RQB3 mice transgenic for a E(3'! gene express an intact E(3d/Eak molecule. Upon immunization with bovine CII to induce arthritis, these transgenic mice showed a marked decrease in both incidence and severity of disease. This protective phenomenon was shown to be dependent on specific E(3 molecules, where only the E(3d and F(3" were associated with protection while other FI(3 genes have no effect on CIA. Further analysis of the E|3d molecules has revealed that the HV3 region of the first domain in this molecule probably contains critical elements involved in the protection phenomenon. Lymph node cells from B10.RQB3 and B10.Q (H-24) respond to a peptide (65-79) encompassing the HV3 region of the Epd and E(3S molecules, while peptides from E|3b'k and E(3P failed to induce a T cell response. Thus, a correlation exists between the T cell response to the HV3 peptides and protection of the corresponding H-2E molecule against CIA, implicating that these peptides bind to the H-2A molecules and thereby mediate the protection effect. H-2A polymorphisms also have been suggested to play a role in the Ep-mediated CIA protection. CIA-susceptible B10.RIII (H-2r) mice transgenic for E(3li fail to protect mice from CIA and fail to mount a T cell response when lymph node cells are challenged with the E(3d 65-79 peptide, implying that the F|3d mediated protection is targeted to the H-2q molecule and not the H-2r.

In addition to a susceptible MHC haplotvpe, T cells expressing specific Vp chains are also important in CIA susceptibility. TCR involvement was first implicated by the observation that SWR mice, which possess a susceptible haplotype (H-21') but have a genomic deletion of 50% of their TCR-Vl4 genes, remain resistant to CIA. When SWR mice were crossed to BIO mice, which are resistant to CIA due to their nonsusceptible MHC haplotype (H-2h) but possess a normal repertoire of V(} genes, the F1 offspring developed CIA, demonstrating gene complementation. The influence of TCR-V^s on CIA has also been demonstrated using TCR-V(3 congenic mice strains. Products of the minor lymphocyte-stimulat-ing (Mis) loci have been shown in part to regulate the expression of specific Vp TCRs by T cells. Mice which have a clonal deletion of T cells because of certain Mis loci (e.g. mammary tumor virus), show a reduction in the incidence of CIA. For example, CIA-susceptible B10.Q (H-2% Mls-lb) have a normal TCR repertoire, while CIA-resistant BALB.D2 (H-2d, Mls-T1) do not possess T cells bearing V(46, Vn7,

Vp8.2, or Vp9 TCRs due to clonal deletion. An F1 cross between these mice (H-2M>) has a deletion of T cells utilizing the specific Vp genes mentioned above and shows a lower incidence of CIA. In summary, the absence of T cells expressing certain V^ TCRs, either by clonal deletion via Mis gene products or genomic deletion, clearly affects susceptibility to CIA.

Susceptibility to CIA is also dependent on the source of type II collagen. Immunization with either bovine, deer or porcine collagen can induce arthritis in H-21' and H-2r mice. However, B10.RIII (H-2r) mice are resistant to disease induction with chick CII. B10.Q mice are resistant when immunized with porcine CII but are susceptible to chick CII. These findings suggest that at least two different collagen epitopes have the capacity to induce disease. Identification of such arthritogenic epitopes on CII has been pursued using cyanogen bromide fragments. A 245 amino acid CB fragment (CB11) from chick type II collagen has been shown to induce CIA in DBA/1 mice. Additionally, autoantibodies directed against murine CII are predominantly restricted to determinants on CB11, suggesting this fragment may contain arthritogenic epitopes. Although synthetic peptides corresponding to amino acids 122-147 and 245-270 of the CB11 molecule have been shown to induce tolerance and/or inhibit CIA, the arthritogenic potential of these peptides to date have yet to be demonstrated.

Immunomodulation of CIA

CIA in mice and rats has provided an excellent model for the development of several novel therapies of arthritis. These include the use of CII oral tolerance, antibodies and agents that affect T cells, MHC molecules, and the TCR. Modulation of cytokine levels in arthritic mice has also proved to be fruitful in the therapy of disease. Therapeutic protocols to date for the treatment of CIA are presented in Table 2. Ali of the above-mentioned interventions are able to

Table 2 Therapeutic protocols used for treatment of CIA

Anti-MHC class II, Anti-CD4 Anti-uß TCR, Anti-Vp TCR Anti-CD40, Anti-gp39

IL-1R antagonist protein, IL-1R:lgG fusion protein Soluble IL-2R, IL-4, IL-10, IL-13 Anti-TNFa, TNFR, TNFR:lgG1 fusion protein Recombinant human TNFR:Fc fusion protein Oral tolerance (native type II collagen or peptide) H-2Eß transgene, DR2 (DRB1*1502) transgene modulate disease to some extent and a few of the listed agents are currently in clinical trials for human RA.

Was this article helpful?

0 0
Treating Rheumatoid Arthritis With Herbs Spices Roots

Treating Rheumatoid Arthritis With Herbs Spices Roots

Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.

Get My Free Ebook

Post a comment