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During evolution, the development of secondary lymphoid organs has evolved as a strategy to promote adaptive immune responses at sites of antigen sequestration. Mesenteric lymph nodes (LNs) and Peyer's patches (PPs) are localized in proximity to mucosal surfaces, and their development is coordinated by a series of temporally and spatially regulated molecular events involving the collaboration between hematopoietic, mesenchymal, and, for PPs, epithelial cells. Transcriptional control of cellular differentiation, production of cytokines as well as adhesion molecules are mandatory for organogenesis, recruitment of mature leukocytes, and lymphoid tissue organization. Similar to fetal and neonatal organogenesis, lymphoid tissue neoformation can occur in adult individuals at sites of chronic stimulation via cytokines and TNF-family member molecules. These molecules represent new therapeutic targets to manipulate themicroenvironment during autoimmune diseases. [ABSTRACT FROM AUTHOR]

Hepcidin is a cationic amphipathic peptide made in the liver, released into plasma and excreted in urine. Hepcidin is the homeostatic regulator of intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores, but it is also markedly induced during infections and inflammation. Under the influence of hepcidin, macrophages, hepatocytes, and enterocytes retain iron that would otherwise be released into plasma. Hepcidin acts by inhibiting the efflux of iron through ferroportin, the sole known iron exporter that is expressed in the small intestine, and in hepatocytes and macrophages. As befits an iron-regulatory hormone, hepcidin synthesis is increased by iron loading, and decreased by anemia and hypoxia. Hepcidin is also rapidly induced by cytokines, including IL-6. The resulting decrease in plasma iron levels eventually limits iron availability to erythropoiesis and contributes to the anemia associated with infection and inflammation. The decrease in extracellular iron concentrations due to hepcidin probably limits iron availability to invading microorganisms, thus contributing to host defense. [ABSTRACT FROM AUTHOR]

The skin is populated with Langerhans cells, thought to be efficient, potent antigen-presenting cells, that are capable of inducing protective immunity by targeting antigen delivery to the skin. Delivery to the skin may be accomplished by active delivery such as intradermal injection, use of patches or a combination of a universal adjuvant patch with injections. The robust immunity induced by skin targeting can lead to dose sparing, novel vaccines and immune enhancement in populations with poorly responsive immune systems, such as the elderly. Vaccine delivery with patches (transcutaneous immunization), may allow self-administration, ambient temperature stabilization and ease of storage for stockpiling, leading to a new level of efficient vaccine distribution in times of crisis such as a bioterror event or pandemic influenza outbreak. The use of an adjuvant (immunostimulant) patch with injected vaccines has been shown in clinical studies to enhance the immune response to an injected vaccine. This can be used for dose sparing in pandemic influenza vaccines in critically short supply or immune enhancement for poor responders to flu vaccines such as the elderly. Transcutaneous immunization offers a unique safety profile, as adjuvants are sequestered in the skin and only delivered systemically by Langerhans cells. This results in an excellent safety profile and allows use of extremely potent adjuvants. The combination of the skin immune system, safe use of potent adjuvants and ease of delivery suggests that skin delivery of vaccines can address multiple unmet needs for mass vaccination scenarios. [ABSTRACT FROM AUTHOR]

The availability of vaccines that contain both measles and rubella components allows for the elimination of both diseases. Although routine infant vaccination with rubella vaccine has had profound effects on the incidence of both acquired and congenital rubella, mass vaccination rapidly stops circulation of the virus and prevents paradoxical increases in susceptibility of women that might result from decreased exposure in childhood. Whereas routine rubella vaccination has eliminated the infection from many developed countries, mass vaccination has rapidly accomplished the same goal in Latin America and the Caribbean, and is being applied in other developing country areas. [ABSTRACT FROM AUTHOR]

Effective vaccines against poliomyelitis became available in the mid-1950s and early 1960s. Mass campaigns were an integral part of early control efforts. Thereafter, polio vaccines were used largely in routine childhood programs. The resolution in 1988 to eradicate polio globally led to the development of appropriate strategies to achieve this goal, including mass vaccination campaigns (i.e., national immunization days, sub-national immunization days and mop-up activities), to achieve the highest possible coverage in the shortest possible time. Unlike other vaccines, mass campaign use of oral poliovirus vaccine enhances the immunogenicity of this vaccine, primarily due to: (1) the decrease in the prevalence of other enteroviruses that potentially interfere with seroconversion; and (2) the secondary spread of vaccine virus from vaccinees to close contacts, resulting in seroconversion of some unvaccinated contacts. To reach the highest possible coverage, detailed planning, meticulous execution, careful supervision and standardized monitoring are critical. A number of innovative approaches to improve the quality and/or coverage have become the ‘standard' of supplemental immunization activities. These mass campaigns have led to dramatic decreases in the incidence of polio. This chapter reviews the scientific, operational and programmatic data on mass campaign use of polio vaccines, and summarize the lessons learnt from implementing the mass vaccination strategies used to eradicate poliomyelitis globally. [ABSTRACT FROM AUTHOR]

Measles ranks fifth among the five major childhood conditions which are responsible for 21% of all deaths in low and middle-income countries. Measles immunization is considered the most cost-effective public health intervention in the world. In recent years, there has been a critical need to identify alternative routes of measles immunization, which are rapid, reliable, cost-effective, needle-free, and suitable for use in mass campaigns. Aerosol administration of measles vaccines in mass campaigns was first proposed by Dr. Albert Sabin. We review the different clinical trials that have been conducted using the classic Mexican device as well as issues regarding vaccine strain, presentation, and manufacturer. Results of clinical trials indicate that the method is safe and immunogenic in infants and school age children. The viral inoculum will probably need to be increased when administered to infants. From the logistical point of view, the use of the aerosol method has not been evaluated in routine immunization although feasibility of its routine implementation was proved in mass campaigns in Mexico. Cost savings will probably be demonstrated. As to licensure, its compliance with the appropriate international regulatory requirements for medical aerosol delivery devices is in process. [ABSTRACT FROM AUTHOR]

Measles is one of most infectious diseases. Before the introduction of the measles vaccine, practically all children in the long run contracted measles. By the end of the 1980s most countries of the world had incorporated measles vaccine into their routine vaccination programs. Globally, some 800,000 deaths due to measles still occur every year, half of them in Africa. Eradication of measles would play an important role in improving child survival. The goal to eradicate measles from the Americas was set by the Pan American Sanitary Conference in 1994. Progress to date has been remarkable. Measles is no longer an endemic disease in the Americas and interruption of transmission has been documented in most countries. As of August 2005, 3 years have elapsed since the detection of the last indigenous case in Venezuela in September 2002. This experience shows that interruption of measles transmission can be achieved and sustained over a long period of time and that global eradication is feasible if appropriate strategy is implemented. Even in a new paradigm in which eradication is not followed by the discontinuation of vaccination, eradication of measles will be a good investment to avoid expensive epidemics and save the almost one million children that die every year to infection with the measles virus. It is not a dream to think that we will se a world free of measles by the year 2015. [ABSTRACT FROM AUTHOR]

Influenza virus causes annual epidemics and occasional pandemics. Frequent mutations in circulating influenza strains ("antigenic drift") result in the need for annual vaccination. More than two-thirds of persons in the U.S. are recommended for annual vaccination. Because influenza vaccine is available seasonally, mass vaccination strategies are well suited to its delivery. Although doctors offices are the most frequent setting for influenza vaccination overall, workplaces, clinics, and community sites (retail stores and pharmacies) also are common vaccination settings. Influenza vaccination also is delivered in mass vaccination clinics to health care workers and military personnel. Universal influenza vaccination, which has been recommended as a strategy to improve prevention by increasing vaccination coverage and providing indirect protection of adults by decreasing infection and transmission among children, would require expanded use of mass vaccination, for example in schools, as well as in the community. Influenza pandemics occur when a new influenza A subtype is introduced into the population ("antigenic shift"). Most or all of the population is susceptible to the pandemic virus and two doses of vaccine may be needed for protection. U.S. pandemic preparedness and response plans indicate that the entire population should be vaccinated beginning with defined priority groups including those who provide essential services including healthcare and those at highest risk of severe illness and death. Pandemic influenza vaccination will occur primarily through the public sector in mass clinic settings. Vaccination program planning must consider issues including coordination, staffing, clinic location and lay-out, security, record keeping, and communications. Exercising vaccination clinics is important for preparedness and can be done in the context of annual influenza vaccination. [ABSTRACT FROM AUTHOR]

Mainland France is considered as a low endemicity area for hepatitis B, but the French Caribbean and Pacific territories are classified into areas of intermediate and high endemicity. In France vaccination programmes aimed at high-risk groups were started in 1982 (including health care workers and patients receiving blood products) and the immunization of babies born of hepatitis B virus surface antigen (HBsAg)-positive mothers was reinforced in 1992. Considering the drawbacks and limited effect of targeted vaccination policies, universal vaccination targeted particularly to the preadolescent and adolescent population was initiated in 1994. In 1995, hepatitis B virus (HBV) vaccination was included in the infant immunization schedule. However, the emotion generated by the claim that HBV vaccination could have led to the development of central nervous system demyelinating disorders resulted in a marked decline of HBV vaccine use, both in the pediatric (23.3% vaccination coverage in children less than 13 years old) and in the adult population. The current coverage rates are likely to be insufficient to bring about a significant reduction in the control of hepatitis B in France. The success of universal immunization is highly dependent on reinstating the confidence of the public and health care professionals in the safety and efficacy of hepatitis B vaccines. [ABSTRACT FROM AUTHOR]

When first introduced in 1992 the hepatitis A vaccine was recommended for individuals at high risk of exposure. This policy was not expected to have a significant impact on disease incidence at population level in view of the epidemiology of the hepatitis A virus (HAV).More recently two countries, Israel and Bahrain, and regions or subpopulations in others (Australia, China, Byelorussia, Italy, Spain, US) have embarked upon more ambitious vaccination programmes that aim to immunize whole birth cohorts. After a brief survey of the virology and epidemiology of HAV, the disease burden it inflicts and a short history of the development of HAV vaccines — both live (in China) and killed vaccines are available — the vaccination programmes introduced in the countries mentioned above are described. The results have been spectacular: disease incidence, not only in the vaccinated cohorts but also in the whole population, have plummeted within a few years of the start of mass vaccination. There is now convincing evidence that the vaccine confers herd immunity if the main spreaders of the virus are targeted for immunization. This finding should encourage other countries to start mass vaccination programmes against HAV, particularly as pharmacoeconomic studies are beginning to show that such a strategy could be a cost-effective way of controlling the disease. It is now even conceivable to eradicate HAV. In fact, this should be easier to achieve than polio eradication as HAV vaccines confer more durable immunity than polio vaccines. However, the global disease burden of HAV is generally thought not to be high enough to justify such an undertaking in the foreseeable future. [ABSTRACT FROM AUTHOR]

Diphtheria is a contagious upper respiratory illness that was a major cause of childhood mortality in the prevaccine era. In the early twentieth century, an effective toxoid vaccine was developed. Implementation of childhood vaccination virtually eliminated diphtheria from developed countries after the Second World War and implementation of the Expanded Program on Immunization in developing countries led to rapid declines in diphtheria globally in the 1980s. However, in the 1990s, a massive epidemic of diphtheria spread throughout the countries of the former Soviet Union. Unlike the prevaccine era, most cases of severe disease and deaths were reported among adults. Multiple factors contributed to the epidemic, including increased susceptibility among both adults and children; suboptimal socioeconomic conditions; high population movement; and delay in implementing appropriate control measures. Mass immunization was the key element in the epidemic control strategy developed and implemented in a well-coordinated response by an international public health coalition. This strategy focused on rapidly raising population immunity of both adults and children; the immunization of more than 140,000,000 adults and adolescents and millions of children successfully controlled the epidemic. While improved coverage of children in developing countries with diphtheria toxoid has led to progressive decreases in diphtheria; eradication is unlikely in the foreseeable future and gaps in immunity among adult population exist or are developing in many other countries. Routine childhood immunization with diphtheria toxoid is the key to controlling diphtheria while the role of routine adult reimmunization is less established; mass immunization will remain an important control measure for widespread diphtheria outbreaks. [ABSTRACT FROM AUTHOR]

A mass immunization campaign is a rapid vaccination intervention across age groups as opposed to provision through routine vaccination at a specified age attainment. Some countries use campaigns routinely as they have experience that shows that in their health systems higher coverage can be reached through campaigns than by routine service provision. Whilst many industrialized and non-industrialized countries have introduced new vaccines into their routine programme, the UK is unusual in deliberately doing this via campaigns. A number ofmass immunization campaigns have been implemented in the UK, either integrated into the routine immunization programme such as the annual influenza immunization campaign; as a catch-up campaign alongside the introduction of a new vaccine into the routine vaccination schedule (MMR, Haemophilus influenzae b, Meningococcal C conjugate vaccine); or as a one-off campaign, to boost immunity in a particular age group, without introducing the vaccination into the schedule routinely at that age (Haemophilus influenzae b). Campaigns require intense planning at national and local level with leadership to achieve propermanagement.Although the components of an immunization campaign can be described separately-strategic planning, vaccine supply, communication and surveillance; for a programme to be successful integrated planning is essential. [ABSTRACT FROM AUTHOR]

Mass immunization involves delivering immunizations to a large number of people at one or more locations in a short interval of time. Good mass immunization programs apply planning and quality standards that maximize return on resources invested and provide the greatest individual benefits when immunizing many people in a short period of time. These programs can be used to counter contagious outbreaks, adopted as a repeated means of sustained healthcare delivery, or applied where many people move through a specific place in a short interval of time. Relevant quality standards address appropriate facilities and supplies, training of professional and paraprofessional staff, education of potential vaccinees and methods to screen them for contraindications to immunization, safeguards against anaphylaxis and syncope, documentation, safety surveillance, and a quality-improvement program. Successful mass immunization programs require early planning that builds on existing competencies. As the number of available vaccines increases, prioritizing which vaccines to administer during mass campaigns requires consideration of effectiveness, safety, and a cost-benefit equation from both the individual and community perspectives. Mass immunization campaigns aim to maximize the health of a population, but such campaigns need to be customized based on individual contraindications to immunization. Mass immunization programs need to be conducted ethically, with considerations of benefit versus risk and the need for detailed education of healthcare workers and vaccinees. [ABSTRACT FROM AUTHOR]

The Smallpox Eradication Program, initiated by the WHO in 1966, was originally based on mass vaccination. The program emphasized surveillance from the beginning, largely to track the success of the program and further our understanding of the epidemiology of the disease. Early observations in West Africa, bolstered by later data from Indonesia and the Asian subcontinent, showed that smallpox did not spread rapidly, and outbreaks could be quickly controlled by isolation of patients and vaccination of their contacts. Contacts were usually easy to find because transmission of smallpox usually required prolonged face-to-face contact. The emphasis therefore shifted to active searches to find cases, coupled with contact tracing, rigorous isolation of patients, and vaccination and surveillance of contacts to contain outbreaks. This shift away from mass vaccination resulted in an acceleration of the program's success. [ABSTRACT FROM AUTHOR]

With increased demand for smallpox vaccination during the nineteenth century, vaccination days—early mass vaccination campaigns—were conducted over time-limited periods to rapidly and efficiently protect maximum numbers of susceptible persons. Two centuries later, the challenge to rapidly and efficiently protect populations by mass vaccintion continues, despite the strengthening of routine immunization services in many countries through the Expanded Programme on Immunization strategies and GAVI support. Perhaps the most widely accepted reason for mass vaccination is to rapidly increase population (herd) immunity in the setting of an existing or potential outbreak, thereby limiting the morbidity and mortality that might result, especially when there has been no routine vaccination, or because populations have been displaced and routine immunization services disrupted. A second important use of mass vaccination is to accelerate disease control to rapidly increase coverage with a new vaccine at the time of its introduction into routine immunization programmes, and to attain the herd immunity levels required to meet international targets for eradication and mortality reduction. In the twenty-first century, mass vaccination and routine immunization remain a necessary alliance for attaining both national and international goals in the control of vaccine preventable disease. [ABSTRACT FROM AUTHOR]

The mucosal regions of the body are responsible for defense against environmental pathogens. Particularly in the lumen of the gut, antibody-mediated immune responses are critical for preventing invasion by pathogens. In this chapter, we review structural studies that have illuminated various aspects of mucosal immunity. Crystal structures of IgA1-Fc and IgA-binding fragments of the polymeric immunoglobulin receptor and FcαRI, combined with models of intact IgA and IgM from solution scattering studies, reveal potential mechanisms for immune exclusion and induction of inflammatory responses. Other recent structures yield insights into bacterial mechanisms for evasion of the host immune response. [ABSTRACT FROM AUTHOR]

In conventionally reared mice germinal centers (GCs) are chronically induced in Peyer's patches (PP), mesenteric lymph node (MLN), and isolated lymphoid follicles (ILF) of gut-associated lymphoid tissues (GALT), as a result of continuous B cell stimulation by commensal bacteria. It is generally thought that BCR-mediated antigen recognition controls the recruitment and thus selection of B cells within GALT GCs. However, recent results challenge this view and suggest that engagement of innate immune receptors by microbial antigens promotes B cell recruitment to, and maintenance within, the GC, irrespective of BCR specificity. We propose a scenario in which microbial determinants presented by follicular dendritic cells (FDCs) to innate receptors on B cells within the GC support the survival and concomitant expansion of somatically mutated, IgA-class-switched B cell clones expressing a variety of BCR specificities. From this pool, B cell mutants recognizing gut-derived antigens through their BCR are either, in GCs, drawn into the process of affinity maturation, or, in the lamina propria (LP) of the gut, locally selected to differentiate into plasmablasts, thus contributing to the continuous production of IgA antibodies required for an efficient protection against commensal and pathogenic microorganisms. [ABSTRACT FROM AUTHOR]

Our intestine is colonized by an impressive community of commensals that has profound effects on the immune functions. The relationship between gut microbiota and the immune system is one of reciprocity: Commensals have important contributions in nutrient processing and education of the immune system, and, conversely, the immune system, particularly gut-associated lymphoid tissues (GALT), plays a key role in shaping the repertoire of gut microbiota. In this chapter we attempt to discuss the mechanisms that underlie this reciprocity and emphasize the key role of mucosal IgA in maintenance of an appropriate segmental distribution of microbiota, which is necessary for immune homeostasis. [ABSTRACT FROM AUTHOR]

The lower intestine of mammals is colonised by a dense flora composed mainly of non-pathogenic commensal bacteria. These intestinal bacteria have a wide-ranging impact on host immunity and physiology. One adaptation following intestinal colonisation is increased production and secretion of polyspecific intestinal IgA. In contrast to the strong mucosal immune response to bacterial colonisation, the systemic immune system remains ignorant of these organisms in pathogen-free mice. Small numbers of bacteria can penetrate the epithelial surface overlying Peyer's patches and survive in dendritic cells to induce IgA by T-dependent and T-independent mechanisms. These dendritic cells loaded with live commensal organisms can home to the mesenteric lymph nodes but do not reach systemic secondary lymphoid structures, so induction of mucosal responses is focused inmucosal lymphoid tissues. The secretion of antibodies across the intestinal epithelial surface in turn limits the penetration of commensal organisms, but this is one of many mechanisms which adapt the intestinal mucosa to co-existence with commensal bacteria. [ABSTRACT FROM AUTHOR]

The adaptive immune system—with its remarkable ability to generate antigen-specific antibodies and T lymphocytes against pathogens never before "seen" by an organism—is one of the marvels of evolution. However, to generate these responses, the adaptive immune system requires activation by the innate immune system. Toll-like receptors (TLRs) are perhaps the best-understood family of innate immune receptors for detecting infections and stimulating adaptive immune responses. TLR9 appears to have evolved to recognize infections by a subtle structural difference between eukaryotic and prokaryotic/viral DNA; only the former frequently methylates CpG dinucleotides. Used as vaccine adjuvants, synthetic oligodeoxynucleotide (ODN) ligands for TLR9—CpG ODN—greatly enhance the speed and strength of the immune responses to vaccination. [ABSTRACT FROM AUTHOR]

To exert immunological activity, T and B cells must leave the blood and enter different extravascular compartments in the body. An essential step in this process is their adhesion to microvascular endothelium and subsequent diapedesis into a target tissue. Naive and effector/memory T and B cells possess distinct repertoires of traffic molecules that restrict their ability to interact with specialized microvessels in different anatomic compartments and thus exhibit distinct patterns of migration. In addition, antigen-experienced lymphocytes are subdivided into different subsets based on their expression of characteristic sets of adhesion receptors that favor their accumulation in certain target organs, such as the skin and the gut. This article focuses on recent discoveries that have broadened our understanding of the "imprinting" mechanisms responsible for the generation of tissue-specific effector/memory lymphocytes, especially in the intestine. We discuss how gut-specific homing is acquired, maintained, and modulated and how these mechanisms might be harnessed to develop improved vaccine protocols and treatments for intestinal autoimmune diseases. [ABSTRACT FROM AUTHOR]

During fetal development, lymphoid tissue inducer cells (LTis) seed the developing lymph node and Peyer's patch anlagen and initiate the formation of both types of lymphoid organs. In the adult, a similar population of cells, termed lymphoid tissue inducer-like cells (LTi-like cells), supports the formation of organized gut-associated lymphoid tissue (GALT) in the intestine, including both isolated lymphoid follicles (ILFs) and cryptopatches (CPs). Both LTi and LTi-like cells require expression of the transcription factor RORγt for their differentiation and function, and mice lacking RORγt lack lymph nodes, Peyer's patches, and other organized GALT. In ILFs and cryptopatches, LTi-like cells are in close contact with different populations of intestinal dendritic cells (DCs), including a subpopulation recently shown to extend dendrites and sample luminal microflora. This interaction may allow for communication between the intestinal lumen and the immune cells in the lamina propria, which is necessary for maintaining homeostasis between the commensal microflora and the intestinal immune system. The potential functional implications of the organization of LTi-like cells, DCs, and lymphocytes in the lamina propria are discussed in the context of maintenance of homeostasis and of infectious diseases, particularly HIV infection. [ABSTRACT FROM AUTHOR]

Host organisms live in intimate contact with indigenous microflora. The interactions between the host and commensal microbiota are highly complex and heterogeneous. A growing body of evidence indicates that commensal symbionts provide many benefits to the host physiology, particularly in the gastrointestinal system. The molecularmechanisms of themutualistic interactions between the host and commensals are largely unknown but can be due either to bioactivity of the commensals or to the reaction of the host immune system to the commensal-derived products. Recent advances in our understanding of the innate immune system allow re-evaluation of some of the older findings regarding the mechanisms of benefits conferred by microflora. Here we review the examples of the benefits of host-commensal interactions that are due to recognition of commensal microbial products by the host innate immune system. [ABSTRACT FROM AUTHOR]

T cell responses to viral infections can mediate either protective immunity or damaging immunopathology. Viral infections induce the proliferation of T cells spe cific for viral antigens and cause a loss in the number of T cells with other specificities. In immunologically naïve hosts, viruses will induce T cell responses that, dependent on the MHC, recognize a distinct hierarchy of virus-encoded T cell epitopes. This hierarchy can change if the host has previously encountered another pathogen that elicited amemory pool of T cells specific to a cross-reactive epitope. This heterologous immunity can deviate the normal immune response and result in either beneficial or harmful effects on the host. Each host has a unique T cell repertoire caused by the random DNA rearrangement that created it, so the specific T cells that create the epitope hierarchy differ between individuals. This "private specificity" seems of little signifi-cance in the T cell responseof a naïvehost toinfection, but it is of profoundimportance under conditions of heterologous immunity, where a small subset of a cross-reactive memory pool may expand and dominate a response. Examples are given of how the private specificities of immune responses under conditions of heterologous immunity influence the pathogenesis of murine and human viral infections. [ABSTRACT FROM AUTHOR]

T cell memory induced by prior infection or vaccination provides enhanced protection against subsequent microbial infections. The processes involved in generating and maintaining T cell memory are becoming better understood due to recent technological advances in identifying memory T cells and monitoring their behavior and function in vivo. Memory T cells develop in response to a progressive set of cues—starting with signals from antigen-loaded, activated antigen-presenting cells (APCs) and inflammatory mediators induced by the innate immune response, to the poorly defined subsequent signals triggered as the immune response wanes toward homeostasis. The persistence of the resting memory T cells that eventually develop is regulated by cytokines. This chapter discusses recent findings on how memory T cells develop to confer long-term protective immunity. [ABSTRACT FROM AUTHOR]

In this review, we will discuss the cascade of cellular and molecular events in the immune response to protein antigens that regulate the development of high-affinity B cell memory. The behavior of antigen-experienced pMHCII+ dendritic cells DCs and the dynamics of their interaction with specific T-helper (Th) cells define the first developmental checkpoint for adaptive immunity in vivo. Recent studies provide insight into the basis of Th cell clonal selection and the requirements and consequences of antigen priming in this responsive Th cell compartment. Antigen-specific Th cells expand to become the cognate regulators of effector B cell responses and initiators of the germinal center reaction and memory B cell development. We will discuss the development and role of these diverse mixtures of antigen-specific B cells in the control of B cell memory and long-term humoral immunity that underpin effective protein vaccination. [ABSTRACT FROM AUTHOR]

The innate immune system provides many ways to quickly resist infection. The twobest-studieddefenses indendritic cells (DCs) are the productionof protective cytokines—like interleukin (IL)-12 and type I interferons—and the activation and expansion of innate lymphocytes. IL-12 and type I interferons influence distinct steps in the adaptive immune response of lymphocytes, including the polarization of Thelper type 1 (Th1)CD4+ T cells, thedevelopment of cytolytic T cells andmemory, and the antibody response. DCs havemany other innate features that do not by themselves provide innate resistance but are critical for the induction of adaptive immunity. We have emphasized three intricate and innate properties of DCs that account for their sentinel and sensor roles in the immune system: (1) special mechanisms for antigen capture and processing, (2) the capacity tomigrate to defined sites in lymphoid organs, especially the T cell areas, to initiate immunity, and (3) their rapid differentiation or maturation in response to a variety of stimuli ranging from Toll-like receptor (TLR) ligands to many other nonmicrobial factors such as cytokines, innate lymphocytes, and immune complexes. The combination of innate defenses and innate physiological properties allows DCs to serve as amajor link between innate and adaptive immunity. DCs and their subsets contribute to many subjects that are ripe for study including memory, B cell responses, mucosal immunity, tolerance, and vaccine design. DC biology should continue to be helpful in understanding pathogenesis and protection in the setting of prevalent clinical problems. [ABSTRACT FROM AUTHOR]

Mammalian Toll-like receptors (TLRs) play a critical role in detection of invading pathogens as well as triggering of subsequent inflammatory and immune responses. Each TLR recognizes distinct microbial components and activates different signaling pathways by selective utilization of adaptor molecules. The signaling via TLRs is delivered from the cell surface and/or the endosome. Recently, the intracytoplasmic detection system of microbes has been identified in mammals as well. Peptidoglycan breakdown products and double-stranded RNA are sensed by NOD family and RNA helicase domain containing proteins, respectively. Thus, mammals make use of both receptor-type and intracellular proteins as detectors of invading pathogens. [ABSTRACT FROM AUTHOR]

It has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 protein that is involved in production of free oxygen radicals through the NADPH oxidase complex, which opens up a new pathway for therapeutic treatment of inflammatory diseases. In most cases, however, a quantitative trait locus (QTL) is the sum effect of several genes within and outside the QTL, which make positional cloning difficult. Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders. [ABSTRACT FROM AUTHOR]

The etiopathologies of autoimmune diseases are complex. A broad variety of cell types and gene products are involved. However, clinical and experimental evidence suggests that the importance of an individual factor changes during the course of the disease. Factors and cell types that induce acute autoreactivity and initiate an autoimmune disease could be distinct from those that drive a chronic course of that disease. Autoreactive immunological memory, in particular B cell and plasma cell memory, contributes to chronicity through several mechanisms. Formation of autoreactive memory B cells leads to an increase in the numbers of autoreactive cells. In comparison to naïve B cells, these memory B cells show a decreased threshold for activation. Additionally, a fraction of memory B cells express the chemokine receptor CXCR3, which supports their accumulation within chronically inflamed tissues. This may allow their escape from mechanisms for induction of peripheral tolerance. Within the inflamed tissue, inflammatory cytokines and autoantigens provide activation signals that promote plasma cell differentiation and survival. The autoantibodies produced locally by these plasma cells contribute to the severity of inflammation. Together, an autoreactive loop of autoantibody-induced inflammation is formed. Another integral part of immunological memory are long-lived plasma cells. These cells provide persistent humoral antibody memory. Though not all autoantibodies are produced by long-lived plasma cells, these cells have a special impact on immune pathology. Long-lived plasma cells are relatively resistant to existing therapies of immunosuppression and continuously secrete antibodies, without need for restimulation. Long-lived plasma cells provide titers of autoantibodies even during clinically quiescent phases and after immunosuppression. These persisting autoantibody titers, though often low and not causing acute clinical symptoms, are likely to maintain a low level of chronic inflammation and progressive tissue destruction, which reduces the threshold for another break of immunological tolerance. [ABSTRACT FROM AUTHOR]

Following investigations of the pathogenic role of autoantibodies in rheumatic diseases, preclinical and clinical studies suggest a more central role of B cells in the maintenance of the disease process beyond just being precursors of (auto)antibody-producing plasma cells. Detailed analyses have implicated a number of surface molecules and subsequent downstream signalling pathways in the regulation of the events induced by BCR engagement. In this review, we discuss the potential role of molecules involved in altered B cell longevity, especially molecules involved in apoptosis (bcl-2, bcl-x, mutations in the Fas/Fas-L pathway), as well as molecules that might alter activation thresholds of B cells (CD19, CD21, CD22, lyn, SHP, SHIP-1) in the development of autoimmunity. Although focused on intrinsic B cell abnormalities, the complexity of interactions of B cells with other immune cells also makes it possible that increased B cell activation can be induced by distortions in the interaction with other cells. Further delineation of these alterations of B cell function in autoimmune conditions will allow development of more precise B cell-directed therapies beyond drastic B cell depletion, with the potential to improve the risk-benefit ratio of the treatments of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Rheumatic inflammation is driven by sustained specific immunity against self-antigens, resulting in local inflammation and cellular infiltration and, subsequently, in tissue damage. Although the specific autoantigen(s) eliciting the detrimental immune reactions in rheumatic diseases have rarely been defined, it has become clear that the mechanisms resulting in the destruction of tissue and the loss of organ function during the course of the diseases are essentially the same as in protective immunity against invasive microorganisms. Of fundamental importance in initiating, controlling, and driving these specific immune responses are CD4 T cells. Currently available data provide compelling evidence for a major role of CD4 T cells in the initiation and perpetuation of chronic rheumatic inflammation. Consequently, T cell-directed therapies have been employed with substantial clinical success in the treatment of rheumatic diseases. Here, we review current knowledge based on which CD4 T cells can be implicated as the motor of rheumatic inflammation. [ABSTRACT FROM AUTHOR]

The analysis of suppression of cytokines in rheumatoid synovial tissue and fluid pioneered the studies of human cytokines in diseased tissue due to the relative ease of staining samples, even at the height of the inflammatory process. These studies led to the study of synovial cytokine regulation, and the identification of TNF as a therapeutic target, which has been amply validated in clinical trials and now routine therapy. The next key question was how is TNF disregulated in synovium. Are there differences between the mechanisms of synovial TNF production compared to the production of protective TNF during an immune response? Are there differences between the induction of the pro-inflammatory TNF and the anti inflammatory IL-10? The analysis of the interaction of the twomost abundant synovial cells, T lymphocytes andmacrophages has provided interesting clues to new therapeutic approaches based on disrupting T-macrophage interaction. [ABSTRACT FROM AUTHOR]

Dying cells were basically unnoticed by scientists for a long time and only came back into the spotlight roughly 10 years ago. The process of recognition and uptake of apoptotic and necrotic cells is complex and failures in this process can contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we discuss the recognition and uptake molecules which are involved in an efficient clearance of dying cells in early and late phases of cell death. The exposure of phosphatidylserine (PS) is an early surface change of apoptosing cells recognized by several receptors and adaptor molecules. We demonstrated that dying cells have cell membranes with high lateral mobility of PS, which contribute to their efficient clearance. Changes of the glycoprotein composition of apoptotic cells occur later than the exposure of PS. We further observed that complement binding is an early event in necrosis and a rather late event in apoptosis. Complement, C-reactive protein (CRP), and serum DNase I act as back-up molecules in the clearance process. Finally, we discuss how the accumulation of secondary necrotic cells and cellular debris in the germinal centers of secondary lymphorgans can lead toautoimmunity. It is reasonable to argue that clearance defects are major players in the development of autoimmune diseases such as SLE. [ABSTRACT FROM AUTHOR]

The autoinflammatory syndromes are a newly recognized group of immune disorders that lack the high titers of self-reactive antibodies and T cells characteristic of classic autoimmune disease. Nevertheless, patients with these illnesses experience unprovoked inflammatory disease in the absence of underlying infection. Here we discuss recent advances in eight Mendelian autoinflammatory diseases. The causative genes and the proteins they encode play a critical role in the regulation of innate immunity. Both pyrin and cryopyrin, the proteins mutated in familial Mediterranean fever and the cryopyrinopathies, respectively, are involved in regulation of the proinflammatory cytokine, IL-1β, and may influence the activity of the transcription factor, NFκB. NOD2, the Blau syndrome protein, shares certain domains with cryopyrin and appears to be a sensor of intracellular bacteria. PSTPIP1, mutated in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne, interacts both with pyrin and a protein tyrosine phosphatase to regulate innate and adaptive immune responses. Somewhat unexpectedly, mutations in the p55 TNF receptor lead not to immunodeficiency but to dramatic inflammatory diseasse, the mechanisms of which are still under investigation. Finally, the discovery of the genetic basis of the hyper- immunoglobulinemia D with periodic fever syndrome has provided a fascinating but incompletely understood link between cholesterol biosynthesis and autoinflammation. In this manuscriptm, we summarize the current state of the art with regard to the diagnosis, pathogenesis, adn treatment of these inborn errors of the innate immune system. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are frequently postulated to arise as post-infectious phenomena. Here we survey the evidence supporting these theories, with particular emphasis on Crohn's disease and ankylosing spondylitis. Direct proof that infection establishes persistent autoimmunity remains lacking, although it may provoke a prolonged inflammatory response when occurring on a susceptible immunological background. The argument of infective causality is by nomeans trivial, since it carries important consequences for the safety of vaccine development. [ABSTRACT FROM AUTHOR]