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Antibody Fc:

Antibody Fc:
  • Author : Margaret Ackerman,Falk Nimmerjahn
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780123948182
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Summary : Antibody Fc is the first single text to synthesize the literature on the mechanisms underlying the dramatic variability of antibodies to influence the immune response. The book demonstrates the importance of the Fc domain, including protective mechanisms, effector cell types, genetic data, and variability in Fc domain function. This volume is a critical single-source reference for researchers in vaccine discovery, immunologists, microbiologists, oncologists and protein engineers as well as graduate students in immunology and vaccinology. Antibodies represent the correlate of protection for numerous vaccines and are the most rapidly growing class of drugs, with applications ranging from cancer and infectious disease to autoimmunity. Researchers have long understood the variable domain of antibodies, which are responsible for antigen recognition, and can provide protection by blocking the function of their target antigen. However, recent developments in our understanding of the protection mediated by antibodies have highlighted the critical nature of the antibody constant, or Fc domain, in the biological activity of antibodies. The Fc domain allows antibodies to link the adaptive and innate immune systems, providing specificity to a wide range of innate effector cells. In addition, they provide a feedback loop to regulate the character of the immune response via interactions with B cells and antigen-presenting cells. Clarifies the different mechanisms of IgG activity at the level of the different model systems used, including human genetic, mouse, and in vitro Covers the role of antibodies in cancer, infectious disease, and autoimmunity and in the setting of monoclonal antibody therapy as well as naturally raised antibodies Color illustrations enhance explanations of the immune system

Antibody Fc

Antibody Fc
  • Author : Margaret Ackerman,Falk Nimmerjahn
  • Publisher :Unknown
  • Release Date :2013
  • Total pages :363
  • ISBN : 0123948029
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Summary : This book synthesizes the literature on the mechanisms underlying the dramatic variability of antibodies to influence the immune response. The book demonstrates the importance of the Fc domain, including protective mechanisms, effector cell types, genetic data, and variability in Fc domain function.

Antibody Fc

Antibody Fc
  • Author : Theo Rispens,Gestur Vidarsson
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060308
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Summary : Immunoglobulins are a group of closely related glycoproteins composed of 82 to 96% protein and 4 to 18% carbohydrate. In humans, there are five classes of immunoglobulins, which differ in heavy-chain structure. Immunoglobulin G (IgG) is the major class of immunoglobulins in blood and can be further subdivided in subclasses. The four subclasses of IgG were discovered in the 1960s following extensive studies using specific rabbit antisera against human IgG myeloma proteins.1 They are designated IgG1, IgG2, IgG3, and IgG4, in order of decreasing abundance. Several decades of research has revealed subtle but profound differences among the subclasses. Each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, and placental transport (Table 9.1). In addition, IgG antibody responses to different types of antigens or pathogens often lead to marked skewing toward one of the subclasses. On the other hand, selective subclass deficiencies are usually not detrimental to the individual but do sometimes lead to enhanced susceptibility toward specific classes of pathogens. All in all, the acquired variability within the Ig locus seems to have been selected for beneficial changes during evolution for optimizing or fine-tuning the antibody-mediated immune response.

Antibody Fc

Antibody Fc
  • Author : Peter Sun
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060285
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Summary : Molecular mechanisms of antibody-mediated Fc receptor activation have long been an interest in both Fc receptor biology and antibody therapeutics. The structural efforts to elucidate antibody recognition by Fc receptors have led to the generation of several crystal structures of antibody Fc fragments complexed with Fc receptors. Collectively, these structures revealed a conserved receptor binding mode for IgG and IgE, distinct from those for the neonatal Fc receptor (FcRn), protein A, and protein G. Fcγ receptor recognition in the lower hinge region allows enhanced antigen recognition through dimeric Fabs but obligates immune-complex formation for receptor activation. It also provides the basis for Fcγ receptors to differentiate among IgG subclasses. More recently, pentraxins have also been shown to bind and activate Fc receptors, and structural efforts to elucidate pentraxin Fcγ receptor recognition have revealed surprising similarities between pentraxins and immunoglobulins in Fc receptor recognition. This review summarizes the structural findings that formed the basis of modern antibody–Fc receptor biology and recent advances of shared Fc receptor recognition by innate pentraxins.

Antibody Fc

Antibody Fc
  • Author : Victor Raúl Gómez Román,Joseph C. Murray,Louis M. Weiner
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060223
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Summary : Antibody-dependent cellular cytotoxicity (ADCC), also called antibody-dependent cell-mediated cytotoxicity, is an immune mechanism through which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells expressing tumor- or pathogen-derived antigens on their surface. Numerous associations between ADCC activity, Fc receptor polymorphisms, and clinical outcomes have been observed in both the settings of vaccination and monoclonal antibody therapy. Here, the effector cells and receptors involved in ADCC are introduced, followed by a description of the four main stages and mechanisms leading to the antibody-dependent effector-mediated killing of the target cell: (1) Recognition of the target cell and Fc receptor cross-linking on the surface of the effector cell; (2) phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) by cellular src kinases within the effector cell; (3) triggering of three main downstream signaling pathways in the effector cell, resulting in cytotoxic granule polarization and release; and (4) killing of the target cell via the predominant perforin/granzyme cell death pathway. Further, a summary and a discussion are presented in relation to case studies in which in vitro ADCC activity correlates with protection against infectious diseases and outcomes in monoclonal antibody therapy of cancer in vivo . The means by which these mechanisms are currently being exploited by recombinant antibody engineering, and a path toward a future in which designed vaccines take advantage of variant ADCC activity are also discussed. Throughout the chapter, attention is drawn to the fact that, while the majority of ADCC studies have been based on research using peripheral blood mononuclear cells in which NK cells have been assumed to be the main effectors, questions remain unanswered about ADCC mediated by non-NK cell populations in peripheral blood and in mucosal compartments.

Antibody Fc Engineering: Towards Better Therapeutics

Antibody Fc Engineering: Towards Better Therapeutics
  • Author : Tianlei Ying,Rui Gong
  • Publisher :Unknown
  • Release Date :2018-12-21
  • Total pages :229
  • ISBN : 9782889456789
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Summary :

Antibody Fc

Antibody Fc
  • Author : Xiaojie Yu,Kavitha Baruah,Christopher N. Scanlan,Max Crispin
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060315
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Summary : The antibody Fc region is posttranslationally modified by N-linked glycosylation. In immunoglobulin G (IgG), the processing of the glycans is restricted by the presence of extensive interaction with the protein surface. The resulting set of antibody glycoforms exhibit a range of effector functions. In this chapter, we outline the impact of glycosylation on the immune function of antibodies and discuss the implications for monoclonal antibody and intravenous immunoglobulin therapies.

Antibody Fc

Antibody Fc
  • Author : Marije B. Overdijk,Sandra Verploegen,Wim K. Bleeker,Paul W.H.I. Parren
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060346
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Summary : Historically, lack of specificity for cancer cells has been a major problem in cancer treatment; however, the development of monoclonal antibodies (mAbs), which combine high specificity with multiple mechanisms of action (MoAs), started a revolution in anti-cancer treatment options which continues to date. As of January 2013, 15 major antibody products were being marketed for cancer treatment in various countries around the globe, 10 of which are unmodified mAbs, which generally have multiple potential MoAs and may act via direct, Fab-domain-related effects or indirect, Fc-domain-related effects. Fc-domain-related effects consist of immune-mediated effector functions, which include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). ADCC and ADCP depend on the engagement of Fcγ-receptors (FcγR) on immune effector cells by Fc-domains clustered due to antibody–antigen binding. Similarly, CDC depends on the engagement of proteins of the complement system by clustered antibody Fc domains. In this chapter, preclinical and clinical studies with approved anti-cancer mAbs are reviewed, with an emphasis on the role of FcγR-mediated effector functions. The importance of therapeutic antibody–FcγR interactions for human treatment can be deduced from correlations of clinical responses with FcγR polymorphisms, results supported by a wealth of preclinical and in vitro studies.

Fc Mediated Activity of Antibodies

Fc Mediated Activity of Antibodies
  • Author : Jeffrey V. Ravetch,Falk Nimmerjahn
  • Publisher :Unknown
  • Release Date :2019-09-03
  • Total pages :150
  • ISBN : 9783030310530
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Summary : This volume explores several aspects of how antibodies mediate their activity in vivo, ranging from cancer immunotherapy to autoimmunity, infection, and vaccination. Divided into seven chapters, it provides in-depth insights into how antibodies and especially the antibody fragment crystallizable (Fc) domain modulate immune responses and antibody activity. The book begins by discussing evolutionary aspects of how the family of Fc receptors that are the key molecules for antibody activity evolved. In turn, it addresses the molecular and cellular pathways underlying IgG activity in cancer immunotherapy, and focuses on how IgG glycosylation regulates IgG and IgE activity in autoimmunity, allergy and infection. In closing, it presents strategies for developing novel antibody-based vaccination approaches. The book is intended for a very broad readership, including graduate students, postdocs and principal investigators with a basic grasp of immunology.

Antibody Fc

Antibody Fc
  • Author : Robert M. Anthony
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060377
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Summary : IgG antibodies are highly potent molecules, with the unique ability to link foreign particles to innate immune cells. IgG antibodies recognize antigens with high affinity and bind cellular Fc receptors with low affinity individually. These interactions occur in the form of immune complexes, resulting in high-avidity interactions. In fact, the effector functions triggered by IgG antibodies are highly dependent on the type of Fc receptor that is bound; however, many aspects can influence Fc receptor binding by IgG antibodies, including the IgG isotype and the composition of the glycan on the IgG antibody. Further, FcγR expression is not stagnant but instead is affected by the inflammatory milieu. These considerations, and others that affect targeting of IgG Fcs to specific FcγRs to elicit desired effector functions, are discussed herein.

Antibody Fc

Antibody Fc
  • Author : Roy Jefferis
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060384
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Summary : Diversity of antigen-binding specificity may be considered the hallmark of antibodies; however, the human IgG-Fc region also exhibits binding specificity for multiple ligands. Evolution of the IgG-Fc has resulted in the generation of interaction sites for endogenous (self) ligands that recruit and activate mechanisms facilitating the removal and destruction of antibody–pathogen immune complexes. However, pathogens (bacteria and virus) have co-evolved to elaborate IgG-Fc binding proteins that seek to subvert these protective mechanisms. The four human IgG subclasses exhibit differential binding specificity for these ligands, and the choice of IgG subclass for an antibody therapeutic allows selection for a ligand binding profile appropriate for the intended use. The profile of IgG-Fc ligand binding specificities is being extended through the generation and selection among multiple IgG-Fc mutant proteins. Of particular interest has been the development of mutant aglycosylated antibodies that retain or acquire ligand binding activities. This extends possible production vehicles to include prokaryotic systems, although an increased potential for inducing anti-drug antibodies may be a limiting factor.

Antibody Fc

Antibody Fc
  • Author : Falk Nimmerjahn
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060322
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Summary : Autoimmune disorders are characterized by the destruction of self-tissues by the immune system. Multiple checkpoints are in place to prevent autoreactivity under normal circumstances. Co-expression of activating and inhibitory Fc receptors (FcRs) represents such a checkpoint by establishing a threshold for immune cell activation. In many human autoimmune diseases, however, balanced FcR expression is disturbed. Analysis of murine model systems provides strong evidence that aberrant FcR expression can result in uncontrolled immune responses and the initiation of autoimmune disease. This review summarizes these data and explains how this information might be used to better understand human autoimmune diseases and to develop novel therapeutic strategies.

Antibody Fc

Antibody Fc
  • Author : Joseph U. Igietseme,Xiaoping Zhu,Carolyn M. Black
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060360
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Summary : Fc receptor (FcR)-dependent effector functions of antibodies contribute significantly to protective immunity against microbial pathogens and tumors. Therefore, FcR-mediated immunological processes constitute a key component of the immune system’s defense armamentaria for maintaining the biological and physiological integrity of the mammalian host who is yoked with frequent encounters with infections and neoplasia. The direct effector functions that result from FcR triggering are phagocytosis, antibody-dependent cellular cytotoxicity, and induction of inflammation; also, FcR-mediated processes provide immunoregulation and immunomodulation that augment T-cell immunity and fine-tune immune responses against antigens. This plasticity of effector and immunoregulatory functions provides unique opportunities to apply FcR-based platforms and immunotherapeutic regimens for vaccine delivery and drug targeting against infectious and non-infectious diseases. This chapter focuses on the protective immunological processes resulting from antibody or immune complex binding to FcRs on effector cells (i.e., NK cells, macrophages, dendritic cells, PMNs, and eosinophils), as well as innovative strategies to apply these mechanisms in immunotherapy, vaccine, and drug delivery against infectious and non-infectious diseases. Deleterious immune reactivity associated with FcR engagement, including immune complex diseases, allergic reactions due to IgE-mediated activation of mast cells and basophils, or facilitation of microbial infectivity, such as antibody-mediated enhancement of infections, are outside the focus of this review.

Antibody Fc

Antibody Fc
  • Author : Brian Moldt,Ann J. Hessell
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060292
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Summary :

Antibody Fc

Antibody Fc
  • Author : George J. Weiner
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060353
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Summary : Monoclonal antibodies (mAbs), including rituximab, are now a mainstay in the therapy of cancer. Despite their undeniable therapeutic value, there is much we do not fully understand about the mechanisms of action responsible for their anti-tumor effects. These mechanisms are often studied in isolation. In this chapter, we will review the mechanisms of action of anti-cancer mAbs and discuss how they interact. The focus of this discussion will be on rituximab, but similar conclusions can be reached with other mAbs.

Engineering Antibody Fc Domains for Improved Therapeutic Function

Engineering Antibody Fc Domains for Improved Therapeutic Function
  • Author : William James Kelton
  • Publisher :Unknown
  • Release Date :2013
  • Total pages :326
  • ISBN : OCLC:903975045
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Summary : Therapeutic antibodies have achieved exceptional clinical success in the treatment of cancer and other human diseases. Now, new approaches are required to enhance the potency of antibodies to further increase the number of patients responding to therapy. By engineering the antibody Fc domain through mutation of the amino acid sequence, binding affinity to activating or inhibitory Fc receptors on effector cells can be increased to modulate the cellular immune response. However, attaining selectivity for closely related Fc receptors has proved challenging and the technique has not been applied to access the function of antibody isotypes other than IgG. Here we present new methods for enhancing antibody potency using both hybrid IgA/G and aglycosylated Fc domains. In the first instance, a chimeric antibody Fc domain has been created by combining residues from IgA with those from IgG. The new variant, MutD, introduces binding to Fc [alpha] RI while retaining affinity for certain members of the Fc [gamma] R family. ADCC assays show MutD, when part of a full length trastuzumab antibody against Her2 antigen, can kill Her2-overexpressing tumor cell lines as effectively as IgA antibodies. Moreover, MutD shows improved assembly compared to IgA and thus provides access to potent Fc [ alpha] RI function while overcoming the expression and purification barriers that have limited the use of IgA as a therapeutic. Alternatively, aglycosylated antibodies may be engineered for exceptional effector function. Glycans anchored to residue N297 of the antibody IgG Fc domain are typically critical in mediating binding toward the Fc [gamma]Rs. Yet, using a full length bacterial IgG display system, we have isolated aglycosylated Fc1004 with mutations that confer a 160-fold increase in the affinity toward the low affinity Fc [gamma] RIIa-R131 allele as well as high selectivity against binding to the remarkably homologous inhibitory receptor, Fc [gamma] RIIb. Incorporation of this engineered Fc into trastuzumab resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with medium Her2-expressing cancer cells. In vivo testing of Fc1004 using NOD/SCID mouse model, reconstituted by adoptive transfer of leukocytes from Fc [gamma] RIIa-R131 homozygous donors, showed a promising reduction in tumor burden in SkBr-3 Her2+ xenografts.

Antibody Fc

Antibody Fc
  • Author : Stefan S. Weber,Annette Oxenius
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060230
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Summary : In humans and mice there exist a multitude of Fcγ receptors (FcγRs) with different affinities and specificities for the different IgG subclasses. Engagement of FcRs on cells usually results in the initiation of an activating or inhibitory signaling cascade that can lead to multiple effector functions, including phagocytosis of opsonized pathogens or immune complexes. In this chapter, we discuss phagocytic cell types and their respective FcγRs that they utilize to phagocytize IgG-coated particles/pathogens. Furthermore, we discuss downstream signaling mechanisms and resulting effects of FcγR-mediated phagocytosis. Special emphasis is given to the role of FcR-mediated phagocytosis in phagocytes for pathogen uptake, subsequent intracellular localization, and pathogen control.

Antibody Fc

Antibody Fc
  • Author : Andreas Diefenbach
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060254
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Summary : Natural killer (NK) cells are granular lymphocytes that play important roles in immunity against viruses and in the immune surveillance of tumors. In addition to being a potent innate source of IFN-γ, NK cells hold cytoplasmic granula that contain perforin and granzymes involved in cell-mediated cytotoxicity. NK cells express various types of immunoreceptors that are all designed to sense pathological changes of self cells. NK cells differ from lymphocytes of the adaptive immune system, such as T and B cells, because they do not express one major immune recognition receptor generated by recombination of receptor elements. Instead, NK cells express an arsenal of polymorphic inhibitory and activating, germline-encoded immunoreceptors with variegated expression that interact with ligands expressed by self cells. The balance of inhibitory and activating input to an NK cell determines its activation state, and harnessing the power of NK cells by exploiting this polymorphic inhibitory receptor/ligand system has become a constituent of clinical therapies.

Antibody Fc

Antibody Fc
  • Author : Menna R. Clatworthy
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060339
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Summary : Fcγ receptors (FcγR) mediate many effector functions of antibody and are critical for defense against pathogens, including bacteria, viruses, and parasites. A number of single nucleotide polymorphisms have been identified in both activating and inhibitory FcγR genes that affect either the binding affinity for IgG or receptor function. Reviewing the available evidence from murine knockout mice, in vitro studies utilizing human cells, and genetic studies in humans, the current view on the role of FcγR polymorphisms in susceptibility to infection will be summarized here. Genetic studies have often yielded conflicting results, which may be due to small sample size or the inherent difficulties associated with genotyping the FCGR locus, or they may reflect differences in the functional importance of interactions between FcγR and its ligands (IgG versus CRP) in differing clinical manifestations of infectious disease. The engagement of the inhibitory FcγR limits the proinflammatory response initiated by FcγR ligation. FCGR polymorphisms that favor activating FcγR may result in excessive inflammation that is deleterious to the host, despite its efficacy in eliminating the pathogen. Overall, pathogen encounter is likely to be the main factor driving the retention of FCGR polymorphisms within the gene pool. Evidence suggests that potent infections, such as malaria, have exerted a significant evolutionary pressure on the maintenance and prevalence of FcγR polymorphisms in different populations.

Antibody Fc

Antibody Fc
  • Author : Margaret A. Lindorfer,Jörg Köhl,Ronald P. Taylor
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060247
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Summary : The key roles of the complement cascade and cellular Fcγ receptors in the innate and adaptive immune system are well documented. Recognition of soluble or cell-bound IgG-containing immune complexes by either of these two respective effector systems leads to a complex series of separate and non-overlapping inflammatory reactions and cytotoxic processes, each of which serves to remove or destroy opsonized microorganisms or targeted tumor cells. Alternatively, in autoimmune diseases these reactions mediate severe pathologies which are manifested in local or systemic inflammation as well as in tissue injury. For some time, it appeared that these two effector systems functioned independently and did not communicate; however, increasing evidence reveals synergy and feedback control between these two systems. Indeed, danger signals can alert one system leading to cross-communication and cooperation with the other to efficiently eliminate the threat. On the other hand, undesired and deleterious inflammation can be controlled by FcγR-mediated suppression of complement.

Antibody Fc

Antibody Fc
  • Author : Mattias Collin,Mogens Kilian
  • Publisher :Unknown
  • Release Date :2013-08-06
  • Total pages :358
  • ISBN : 9780128060391
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Summary : Immunoglobulins (Igs, antibodies) are key players in adaptive immunity, and pathways mediated through the effector Fc portion of Ig are instrumental in controlling bacterial infections. Therefore, it is not very surprising that bacterial pathogens and commensals through co-evolution with their hosts have learned many tricks to interfere with Fc effector functions. In this chapter, we describe three principally different bacterial strategies to interfere with immunoglobulins: Specific Ig binding, specific or unspecific Ig protelolysis, and, finally, specific and unspecific hydrolysis of functionally important carbohydrates on the immunoglobulins. Elucidating these bacterial immune evasion mechanism evidences bacteria–host co-evolution and provides insight into fundamental aspects of human adaptive immunity and pathogenesis of infection.