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Th17 Wins
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-secreting), Th2 (IL-4- and IL-5-secreting), and Th17 (IL-17-secreting) effectors with a TCR specific for the H/K- ATPase each induced gastritis, transfer of Th17 effector cells caused the most dramatic pathology with 80% of Th17 recipients showing evidence of destructive gastritis at 4 wk after injection, compared with 60% of Th2 recipients and 20% of Th1 recipients. Th17 recipient animals had elevated levels of IgE in the serum and gastritis with robust polymorphonuclear infiltrate containing eosinophils. Cotransfer of polyclonal T regulatory cells (Treg) reduced the incidence and severity of disease in Th1-injected and Th2-injected mice but was not effective at suppressing AIG in the Th17 group. While the major effect of polyclonal Treg in animals was to inhibit proliferation of Th effector cells, the same effector cells were quite capable of proliferating and producing cytokines ex vivo when removed from the influence of Treg. Taken together, the strong inhibitory effect of Treg on some effector cells makes Treg attractive therapeutic targets for autoimmunity unless disease is caused by a Th17 mechanism. Alphabet Soup-IRF3, TRIM21, IFNβ
Type I IFN responses to viral and bacterial infections are of paramount importance to maintaining immunity. The transcription factor IRF3 is integral to mediating the expression of type I IFNs during infection. However, at the end of a pathogen challenge, IFN responses mediated by the expression of IFNβ, for example, must be turned off. Higgs et al. (p. 1780 ) have determined that IRF3 is targeted for proteasomal degradation by the E3 ligase Ro52 (TRIM21) after TLR activation, thus inhibiting IFNβ promoter activity. The authors demonstrated that TRIM21 effects its control by interacting with the IRF3 C-terminal SPRY domain, which causes polyubiquitination and proteasomal degradation of IRF3. TRIM21-mediated IRF3 degradation inhibited IFNβ transcription, an effect that could be reversed with the proteasomal inhibitor MG132. Small hairpin RNA (shRNA) targeting of TRIM21 increased IFNβ production following TLR stimulation with poly(I:C). In murine fibroblasts, TRIM21-targeted shRNA enhanced the production of RANTES, a chemokine dependent on IRF3 for transcription, after infection by Sendai virus. Taken together, these results demonstrate that TRIM21 has a novel role in controlling IRF3 by targeting the transcription factor for proteasomal degradation and thus providing a control mechanism for type I IFN responses.
The Parasite and the Antibody
In an elegant and extensive article by Ghumra et al. (p. 1988 ), the authors have attempted to determine how malaria parasites cause erythrocyte rosetting. Known as a virulence factor in the pathogenesis of severe malaria, erythrocyte rosetting consists of an infected erythrocyte binding uninfected erythrocytes, often in the presence of nonspecific IgM. The authors determined that the parasite protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) from a virulent strain of malaria was the IgM-binding ligand and identified the IgM-binding domain within this protein to be the Duffy binding-like 4β domain (DBL4β). PfEMP1, a variant erythrocyte surface Ag, is encoded by a parasite var gene and expressed at the surface of the infected erythrocyte. Through Ab domain analysis and substitution, the authors found that PfEMP1 binds to the IgM Cµ 4 domain. The amino acid sequence of this IgM domain showed homology with that bound by bacterial Fc-binding proteins on IgG and IgA, suggesting conservation due to important host-microbe interactions. Thus, the authors have shown that PfEMP1 is a polymeric IgM-Fc-binding protein that is similar to bacterial Fc-binding proteins. These findings may lead to elucidating the functional significance of parasite-mediated erythrocyte rosetting.
B-eing Sensitive
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PAP2 Effects in Macrophages
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, as well as the immunomodulatory cytokine IL-10, in a dose-dependent manner. Expression of IL-12, IL-15, and IL-18 was unchanged compared with untreated controls. The NF-
B signaling pathway was determined to be involved in PAP2-mediated macrophage changes, because PAP2 treatment caused nuclear translocation of NF-B and phosphorylation of the IB inhibitory protein. In addition, chemical inhibition of NF-B abrogated PAP2-mediated changes in cytokine production. Primary macrophages from the lung, peritoneum, and peripheral blood, but not the spleen, had similar cytokine responses to PAP2 treatment.
In the companion paper by Viterbo et al. (p. 1959
) the authors determine the molecular characteristics necessary for their observations of PAP2 effects on macrophage cytokine production. As a member of the Reg3 gene family, PAP2 is classified as part of the group 7 C-type lectin-like proteins, and the authors mutated domains important in the C-type lectin-like proteins to determine their efficacy. They found that truncation of the PAP domain in the N terminus of PAP2 did not affect macrophage cytokine production, but truncation of the last 30 residues of the C terminus of PAP2 completely abrogated its function. Two invariant disulfide bonds in the C-type lectin domain fold were found to be important for PAP2-induced macrophage cytokine production. However, the disulfide bond that is observed in long form C-type lectin proteins was not found to be essential for PAP2 influence on macrophage function. The inability of PAP2 mutants to cause translocation of NF-B to the nucleus correlated with their inability to cause changes in macrophage cytokine expression, confirming that PAP2 acts on macrophages through an NF-B-dependent mechanism to modulate the inflammatory environment in pancreatitis. With these two articles, the authors have presented clear evidence of how PAP2 modulates the pancreatic microenvironment and given insight into the biochemical mechanism of how this occurs.
IL-10 Controlling Borrelia
Relapsing fever caused by Borrelia turicatae is characterized by peaks of bacteremia in the blood that are cleared by specific IgM Abs. Previous work has shown that B cell-deficient mice infected with B. turicatae produce high levels of IL-10 that are necessary for controlling bacteremia. In Londoño et al. (p. 2076
), this same group now provides a mechanism by which IL-10 controls bacterial levels through a B cell-independent pathway. Using RAG2–/–/IL-10–/– mice they looked at the effect of B. turicatae infection and found that these mice had higher bacteremia, higher levels of TNF, and early mortality when compared with infected RAG2–/– mice. Increased apoptosis of lymphocytes and splenocytes was also found in infected RAG2–/–/IL-10–/– mice but could be blocked by the neutralization of TNF, which led to increased NK production of IFN-, decreased bacteremia, and decreased mortality. The authors conclude that IL-10 protects animals from high levels of bacteremia during B. turicatae infection by protecting innate immune cells from TNF-induced apoptosis and ultimately controlling spirochetemia.
Drak2, Gatekeeper for Neuroinvasion
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-expressing T cells were elevated in the absence of Drak2. However, the brains of infected Drak2–/– mice had reduced viral loads, and this correlated with lower numbers of CD4+ and CD8+ T cells in the brain compared with wild-type mice. Viral Ags were detected in the T cells isolated from both spleens and brains of the infected mice, suggesting that WNV may be entering the CNS by infecting T cells homing to the brain. However, as T cells in the CNS of WNV-infected Drak2–/– mice were more sensitive to apoptosis, these results suggest that Drak2 promotes T cell survival in the brain during WNV encephalitis and exacerbates disease. Summaries written by Kira R. Gantt, Ph.D.
Related articles in The JI:
B Pathway
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