Scott J. Shapiro

Both Th1 and Th2 Cytokines Affect the Ability of Monoclonal Antibodies To Protect Mice against Cryptococcus neoformans

ABSTRACT Variable-region-identical mouse immunoglobulin G1 (IgG1), IgG2b, and IgG2a monoclonal antibodies to the capsular polysaccharide ofCryptococcus neoformans prolong the lives of mice infected with this fungus, while IgG3 is either not protective or enhances infection. CD4+ T cells are required for IgG1-mediated protection, and CD8+ T cells are required for IgG3-mediated enhancement. Gamma interferon is required for both effects. These findings revealed that T cells and cytokines play a role in the modulation of cryptococcal infection by antibodies and suggested that it was important to more fully define the cytokine requirements of each of the antibody isotypes. We therefore investigated the efficacy of passively administered variable-region-identical IgG1, IgG2a, IgG2b, and IgG3 monoclonal antibodies against intravenous infection withC. neoformans in mice genetically deficient in interleukin-12 (IL-12), IL-6, IL-4, or IL-10, as well as in the parental C57BL/6J strain. The relative inherent susceptibilities of these mouse strains to C. neoformans were as follows: IL-12−/− > IL-6−/− > C57BL/6J ≈ IL-4−/− ≫ IL-10−/−. This is consistent with the notion that a Th1 response is necessary for natural immunity against cryptococcal infection. However, none of the IgG isotypes prolonged survival in IL-12−/−, IL-6−/−, or IL-4−/− mice, and all isotypes significantly enhanced infection in IL-10−/− mice. These results indicate that passive antibody-mediated protection againstC. neoformans requires both Th1- and Th2-associated cytokines and reveal the complexity of the mechanisms through which antibodies modulate infection with this organism.

Immunoglobulin G Monoclonal Antibodies to Cryptococcus neoformans Protect Mice Deficient in Complement Component C3

ABSTRACT Passive administration of monoclonal antibodies (MAbs) to the capsular polysaccharide of Cryptococcus neoformans can alter the course of infection in mice. In a murine model of cryptococcal infection, immunoglobulin G1 (IgG1), IgG2a, and IgG2b switch variants of the anti-capsular 3E5 MAb prolong the survival of lethally infected mice, whereas the 3E5 IgG3 MAb does not protect and in some cases enhances infection, shortening the life spans of infected mice. We examined the role of complement component C3 in Ab-mediated protection by determining the efficacy of the four mouse IgG subclasses against C. neoformans in mice genetically deficient in factor C3 as well as mice acutely depleted of C3. Similar to other complement-deficient animal models, C3−/− mice and mice depleted of C3 by cobra venom factor were more susceptible to C. neoformans infection than control mice, providing further evidence that complement is important in the host defense against the fungus. In the absence of C3, all IgG isotypes prolonged the lives of mice infected with C. neoformans, indicating that protection by IgG does not require the complement pathways. Furthermore, we observed protection with IgG3 in the complement-deficient mice, suggesting that complement is involved in the lack of protection observed with IgG3 in other mouse models.

Fcγ Receptor I- and III-Mediated Macrophage Inflammatory Protein 1α Induction in Primary Human and Murine Microglia

ABSTRACT Microglial cell phagocytic receptors may play important roles in the pathogenesis and treatment of several neurological diseases. We studied microglial Fc receptor (FcR) activation with respect to the specific FcγR types involved and the downstream signaling events by using monoclonal antibody (MAb)-coated Cryptococcus neoformans immune complexes as the stimuli and macrophage inflammatory protein 1α (MIP-1α) production as the final outcome. C. neoformans complexed with murine immunoglobulin G (IgG) of γ1, γ2a, and γ3, but not γ2b isotype, was effective in inducing MIP-1α in human microglia. Since murine γ2b binds to human FcγRII (but not FcγRI or FcγRIII), these results indicate that FcγRI and/or FcγRIII is involved in MIP-1α production. Consistent with this, an antibody that blocks FcγRII (IV.3) failed to inhibit MIP-1α production, while an antibody that blocks FcγRIII (3G8) did. An anti-C. neoformans MAb, 18B7 (IgG1), but not its F(ab′)2, induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase kinase phosphorylation, and MIP-1α release was suppressed by the ERK inhibitor U0126. C. neoformans plus 18B7 also induced degradation of I-κBα, and MIP-1α release was suppressed by the antioxidant NF-κB inhibitor pyrrolidine dithiocarbamate. To confirm the role of FcR more directly, we isolated microglia from wild-type and various FcR-deficient mice and then challenged them with C. neoformans plus 18B7. While FcγRII-deficient microglia showed little difference from the wild-type microglia, both FcγRI α-chain- and FcγRIII α-chain-deficient microglia produced less MIP-1α, and the common Fc γ-chain-deficient microglia showed no MIP-1α release. Taken together, our results demonstrate a definitive role for FcγRI and FcγRIII in microglial chemokine induction and implicate ERK and NF-κB as the signaling components leading to MIP-1α expression. Our results delineate a new mechanism for microglial activation and may have implications for central nervous system inflammatory diseases.

On Hart's Way Out

It is hard to think of a more banal statement one could make about the law than to say that it necessarily claims legal authority to govern conduct. What, after all, is a legal institution if not an entity that purports to have the legal power to create rules, confer rights, and impose obligations? Whether legal institutions necessarily claim the moral authority to exercise their legal powers is another question entirely. Some legal theorists have thought that they do—others have not been so sure. But no one has ever denied (how could they?) that the law holds itself out as having the legal authority to tell us what we may or may not do.

LAW, MORALITY, AND THE GUIDANCE OF CONDUCT

Legal positivism is generally characterized by its commitment to two theses —one negative, the other positive. See, e.g., Jules Coleman, Negative and Positive Positivism, J. L EGAL S TUD . 139 (1982), reprinted in Jules L. Coleman, M ARKETS , M ORALS AND THE L AW 3 (1988). The negative thesis, usually referred to as the “Separability Thesis,” denies any necessary connection between morality and legality. Legal positivists do not require that a norm possess any desirable, or lack any undesirable, moral attributes in order to count as law.

Law, Morality, and Everything Else: General Jurisprudence as a Branch of Metanormative Inquiry*

In this article, we propose a novel account of general jurisprudence by situating it within the broader project of metanormative inquiry. We begin by showing how general jurisprudence is parallel to another well-known part of that project, namely, metaethics. We then argue that these projects all center on the same task: explaining how a certain part of thought, talk, and reality fits into reality overall. Metalegal inquiry aims to explain how legal thought, talk, and reality fit into reality. General jurisprudence is the part of metalegal inquiry that focuses on universal legal thought, talk, and reality.

Book ReviewsBrian Leiter, , ed.Objectivity in Law and Morals.Cambridge: Cambridge University Press, 2001. Pp. 354.

An established but burgeoning line of legal research examines the intersection between law and culture, challenging the traditional assumption that law is autonomous from and functions independently of culture. Growing out of an interdisciplinary perspective, reliant on multi-faceted methodologies, and emphasizing the constitutive character of law, this research suggests not only how legal institutions and rulings shape cultural practices and consciousness but also how cultural practices and consciousness shape the law. In Communities and Law: Politics and Cultures of Legal Identities, Gad Barzilai contributes to and broadens this line of research. A prolific scholar of Israeli law and politics, Barzilai develops a critical communitarian approach that highlights the importance of non-ruling communities and how these communities prove to be both generators and carriers of legal cultures. Barzilai’s contribution is thus founded in more than the rich case studies he offers. Arguing that “communities are crucial pillars in the conjunction of law and politics” (2), Barzilai critiques liberalism’s emphasis on individualism and its neglect of community. Through an in-depth exploration of three non-ruling communities in Israel—Arab-Palestinians, feminist women, and ultra-Orthodox Jews—Barzilai seeks to correct this neglect by examining how non-ruling communities mobilize and resist state law. While non-ruling communities provide the empirical focus of his investigation, Barzilai does not understate the significant, and indeed hegemonic, power of the state. On the contrary, the author emphasizes state domination in general and state-produced legal ideology in particular as forces that constitute legal identity and consciousness. Influenced by Marxism and neo-Marxism, Barzilai argues that states are to be understood as hegemonic producers of legality and culture.