Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, immunological synapse formation and, numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane bound and soluble ICAM-1 isoforms which arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types is poorly understood. In the generation of ICAM-1-deficient mice, two isoform-deficient ICAM-1 mutants were inadvertently produced due to alternative splicing. These mice along with true ICAM-1-deficient mice and newly generated ICAM-1 transgenic mice have provided the opportunity to begin examining the role of ICAM-1 isoforms (singly or in combination) in various disease settings. In this review we highlight the sharply contrasting disease phenotypes using ICAM-1 isoform mutant mice. These studies demonstrate that ICAM-1 immunobiology is highly complex but that individual isoforms, aside from the full-length molecule, make significant contributions to disease development and pathogenesis.

Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum infection and accounts for a large number of malaria fatalities worldwide. Recent studies demonstrated that C5−/− mice are resistant to experimental CM (ECM) and suggested that protection was due to loss of C5a-induced inflammation. Surprisingly, we observed that C5aR−/− mice were fully susceptible to disease, indicating that C5a is not required for ECM. C3aR−/− and C3aR−/− × C5aR−/− mice were equally as susceptible to ECM as wild type mice, indicating that neither complement anaphylatoxin receptor is critical for ECM development. In contrast, C9 deposition in the brains of mice with ECM suggested an important role for the terminal complement pathway. Treatment with anti-C9 antibody significantly increased survival time and reduced mortality in ECM. Our data indicate that protection from ECM in C5−/− mice is mediated through inhibition of MAC formation and not through C5a-induced inflammation.

We showed earlier that experimental autoimmune encephalomyelitis (EAE) in human C-reactive protein (CRP) transgenic mice (CRPtg) has delayed onset and reduced severity compared to wild-type mice. Since human CRP is known to engage Fc receptors and Fc receptors are known to play a role in EAE in the mouse, we sought to determine if FcγRI, FcγRIIb, or FcγRIII was needed to manifest human CRP-mediated protection of CRPtg. We report here that in CRPtg lacking either of the two activating receptors, FcγRI and FcγRIII, the beneficial effects of human CRP are still observed. In contrast, if CRPtg lack expression of the inhibitory receptor FcγRIIB, then the beneficial effect of human CRP is abrogated. Also, subcutaneous administration of purified human CRP stalled progression of ongoing EAE in wild-type mice, but similar treatment failed to impede EAE progression in mice lacking FcγRIIB. The results reveal that a CRP → FcγRIIB axis is responsible for protection against EAE in the CRPtg model.

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Summary Studies have demonstrated that the membrane attack complex (MAC) of complement can evoke seizures when injected directly into rodent brain. In the course of studies examining the role of complement in the development of experimental cerebral malaria (ECM), we observed fewer seizures in mice deficient in C5, a component required for MAC formation. To determine if the MAC contributed to the tonic-clonic seizures characteristic of ECM, we performed long-term video-electroencephalography (EEG) on C5−/− mice with Plasmodium berghei ANKA-induced cerebral malaria and observed significantly reduced spike and seizure frequency compared to wild type mice. Our data suggest a role for the MAC in malaria-induced seizures and that inhibition of the terminal complement pathway may reduce seizures and seizure-related neurocognitive deficits.