Dr. S.G. Deodhare, M.D., F.A.M.S
Former Professor of Pathology, Grant Medical College
and Dean, J.J. Group of Hospitals,
Mumbai.
OUTLINE
Introduction
The Skin as an Immune System
Skin-Associated Lymphoid Tissue (SALT)
Langerhans Cells (LC)
Keratinocytes
T- lymphocytes
Afferent and Efferent Phases of the Skin
Immune System
Recent Advances in SALT Research
Recent Insight into Natural
Killer (NK) Cells
Subpopulations of T Cells
ab T Cells
gd T Cells
Major Populations of B Cells: B1 and B2
Superantigens
Superantigens versus Conventional Antigens
Immunization
Immunization Programmes and Herd Immunity
Impact of Hib Vaccine on Haemophilus influenzae Infection
Rotavirus Vaccine: The Future
Intravenous Immune Globulin in Immunodeficiency Diseases
References
Graphics
Fig. 1
Fig. 2
Fig. 3A
Fig. 3B
INTRODUCTION
The flowering of late-20th century immunology began towards the end of 1950, when the focus shifted from serology to cells. The clonal-selection theory - the idea that lymphocytes are genetically distinct clone - signalled the start of the new era. The new emphasis on immune cells and the simultaneous emergence of molecular biology were the two most powerful influences on immunology since its inception. Within 15 years the synergistic union of new ideas and new techniques resulted in a detailed understanding of the immune response. Moreover, therapeutics in immunology acquired a logical basis. It is no coincidence that transplantation surgery evolved from the impossible to the routine during that time.
The immune system should be considered in the same way as any other organ system: it has structure, organization at a series of levels and functions. It differs in the way its elements are so closely related to other organ systems, yet free to move throughout the whole body.
The immune system has specialized roles in defence against infection. There are two fundamentally different types of responses to invading microbes. Innate (natural) responses occur to the same extent however many times the infectious agent is encountered, whereas acquired (adaptive) responses improve on repeated exposure to a given infection. The innate responses use phagocytic cells (neutrophils, monocytes, and macrophages), cells that release inflammatory mediators (basophils, mast cells and eosinophils), and natural killer cells. The molecular components of innate responses include complement, acute phase proteins and cytokines such as interferons. (Cytokines have the abilities to act in an autocrine, paracrine and manner to promote and facilitate differentiation and proliferation of cells of the immune system).
Acquired response involves the proliferation of antigen-specific B and T cells, which occurs when the surface receptors of these cells bind to an antigen specialized cells, called antigen-presenting cells (APCs), display the antigen to lymphoctes and collaborate with them in the response to the antigen. B cells secrete immunoglobulins, the antigen-specific antibodies responsible for eliminating extracellular microorganisms. T cells help B cells to make antibody and can also eradicate intracellular pathogens by activating macrophages and by killing virally infected cells. Innate and acquired responses usually work together to eliminate pathogens.
Bodily defence against infection is secured through a combination of physical barriers, including the skin, mucous membranes, mucous secretions, and ciliated epithelial cells, and the various components of the immune system. The immune system consists of T lymphocytes, B lymphocytes, natural killer (NK) cells, dendritic and phagocyte cells, and complement proteins. The proteins synthesized and secreted by T, B and NK cells and by the cells with which they interact are referred to as cytokines; several such proteins have been given an official nomenclature as interleukins (ILS). Cytokines have the ability to act in autocrine, paracrine, or endocrine manner to promote and facilitate differentiation and proliferation of cells of the immune system. The immune system also serves to protect against autoimmune disease and malignancy.
THE SKIN AS AN IMMUNE
SYSTEM
The epidermis and in more general terms the skin is not only a physical but also an immunogenic barrier between the host and the environment. This immunologic barrier function of the epidermis is finely tuned to serve needs of the host optimally (Elias PE, Feiingold KR, 1999).
In the last decade, it has become evident that the skin is an active compartment of the peripheral immune system with a distinctive and appropriate set of immune effector modalities adapted specifically to ward off environmental threats from skin. The cellular components of this "Skin-associated lymphoid tissue" (SALT) are keratinocytes, antigen presenting cells such as epidermal Langerhans cells (LC), dermal dendritic cells (DC) and endothelial cells (EC) and the skin-draining lymph nodes.
The Langerhans cells (LC) play an important role in immune surveillance within the skin and, in addition, it now appears that the major epidermal constituent, the keratinocytes, is capable of cytokine secretion and may also present the antigen to T lymphocytes.
Immune cells are found predominantly in the dermis, particularly around the post-capillary vessels in what has been termed as the dermal perivascular unit. Here, in close proximity to the endothelium lie mast cells, macophages, T cells and dendritic cells, some of which are similar to Langerhans cells. At this site immune cells are perfectly poised to respond to signals arising from epidermal injury or infection, and to regulate post-capillary endothelial adhesion molecules. Some 109-1010 T lymphocytes are in the dermal perivascular units.
Skin-Associated Lymphoid
Tissue (SALT)
Langerhans Cells (LC)
It has long been known that the epidermis is a target for various types of immune reactions. This is best evidenced by the demonstration of antibody-mediated acntholysis in pemphigus and T-cell-mediated epidermal cell injury in contact as well as atopic dermatitis. Epidermal cells can subserve immunologic functions per se. This is particularly true for Langerhans cells (LCs), which belong to the family of immunostimulatory dendrtic cells (DCs).
LCs have a dendritic morphology (i.e. have many processes to provide an extensive area of contact) and are derived from the bone marrow as a member of the mononeuclear phagocytic system. LCs are a mobile population with a relatively short turn over. Epidermal residence is only one step in their life cycle. They originate from bone marrow precursors, which upon circulation in the peripheral blood populate the skin. Upon receipt of appropriate activating stimuli (e.g. antigenic challenge), they can leave the cutaneous compartment and migrate to peripheral lymphoid organs where they initiate T cell responses. Having accomplished this task, they initiate events that ultimately result in their own demise.
Langerhans cells have a high level of constitutive expression
of class II MHC molecules, and a current view on their life cycle suggest that
they trap and process antigen within the skin and migrate to the local lymph
node to present peptide antigens to T lymphocytes. Thus LCs as molecules of the
family of antigen presenting cells (APCs), play a pivotal role on the
presentation of antigens introduced into and/or generated in the skin. The
major function of LCs is to provide human immune responses against a wide
variety of antigens including contact allergens, alloantigens, tumour antigens
and microorganisms (Schuler G et al 1997).
Keratinocytes
The most important partner of the Langerhans cells (LCs) is unquestionably the keratinocyte. The majority of cells in the epidermis are keratinocytes. They constitute at least 80% of the total population of nucleated cells in the epidermis. Keratin filaments are a hallmark of the keratinocytes and other epithelial cells.
Examination of the epidermis in inflammatory skin conditions has shown that the keratinocytes express class II MHC molecules and ICAM-1 adhesion molecules under stress. The keratinocyte is also capable of phagocytosis, since this is the process involved in the acquisition of melanin pigment from melanocytes.
Following stimulation of healthy skin keratinocytes in
vitro, several cytokines may be produced: IL-1, IL-6, IL-8, INF-a and
INF-b,
TNF-a and
colony-stimulating factors for myeloid cells (G-CSF, GM-CSF). It is, therefore,
possible to envisage roles for keratinocytes in attracting and anchoring immune
cells (IL-8, CSF, ICAM-1); in exerting cytotoxicity against microorganisms
(IFN- a /b,
TNF-a);
and even in antigen processing and presentation (class II MHC molecules) (Schroder JM, (1998).
T- lymphocytes
In many inflammatory and neoplastic skin diseases, lymphocytes constitute a major portion of the inflammatory infiltrates and not infrequently invade the epidermis. In contrast, a brief microscopic survey of the skin gives the (erroneous) impression of a lymphocyte-free epidermis. Today, we know that the healthy epidermis contains a distinct lymphocyte population that belongs almost exclusively to the T cell lineage.
Upon arrival in the skin and receipt of a renewed antigen's stimulus by APCs (LCs) and co-stimulatory signals of other cells (e.g. keratinocyte-derived IL-7 or IL-15), these sensitised T cells can undergo clonal expansion resulting optimally, in the generation of protective effector mechanisms against the pathogens.
Alternatively, the skin may receive weak stimuli and /or signals (e.g. UV radiation) that prevent LCs from acquiring maturation-related immunostimulatory molecules and, as a consequence, promoting a development of specific allergy or tolerance, to a given antigen. Such tolerizing stimuli can silence nave as well as prime T cells and, in the latter situation, can be delivered by non-professional APCs within the skin, such as keratinocytes and fibroblasts.
It thus appears that the components of skin-associated
lymphoid tissues (e.g. dendritic APCs, cytokine producing keratinicytes, and
skin-homing T cells originating in skin draining peripheral lymph nodes) can
have a dual function. On the one hand, they provide the skin with unique
immunosurveillance mechanisms for the successful combat against pathogens
threatening the integrity of the skin and / or of the host; and on the other
hand, they secure the homeostasis of the integument by preventing the
development of exaggerated, tissue-destructive immune responses against
innocuous moieties such as auto-antigens.
Afferent and Efferent phases of the Skin Immune System
Mechanisms operative in initiation and expansion of cutaneous immune responses are discussed below:
The epidermal and/or interacutaneous application and/or release of antigenic pathogens, (e.g. microorganisms, haptens) affects various cell populations of the skin/epidermis. Antigen presenting cells (LCs, DDCs) pick up the pathogen, process it and re-express it as a peptide/MHC complex on the surface. Keratinocytes, on the other hand, begin to elaborate increased amount of TNF-a and IL-a. This in turn, leads to profound alterations in phenotype and function of LCs as evidenced by their increased expression of MHC antigens, co-stimulatory molecules, and cytokines (IL-1b, IL-6, IL-12), as well as by their emigration from the skin to the paracortical areas of draining lymph nodes. At this site, in lymph nodes, the skin-derived dendritic cells provide activation of stimuli to nave resting T cells surrounding them. This occurs in antigen specific fashion and thus, results in expansion of the respective clones. These primed T cells begin to express skin homing receptor (e.g. cutaneous lymphocyte-associated antigen) as well as receptors for various chemo attractants that promote their attachment to dermal microvascular endothelial cells of inflamed skin and, ultimately, their entry into this tissue. Upon receipt of renewed antigenic stimulus by professional antigen-presenting cells (APCs), the primed cells will expand and display the effector functions needed for the neutralisation and/or elimination of the pathogen.
Recent Advances in SALT Research
Some of the recent advances in SALT research are:
1) the identification of skin-homing sub populations among T cells and LC/DC expressing cutaneous lymphoid-associated antigen (CLA)
2) the T cell-dependent regulation of adhesion molecule expression on EC and their essential role in leukocyte recruitment to cutaneous sites
3) the ability to generate LC/DC from bone marrow or blood precursors, thus opening the possibility to exploit their unique immunostimulatory capacities for therapeutic purposes.
Still, many open questions remain: for example, how SALT discriminates between harmful and harmless antigens, how immune responses in skin are self-limited, and what are the mechanisms that govern the migration of immunocompetent cells from the skin.
RECENT INSIGHT INTO NATURAL
KILLER (NK) CELL FUNCTION
Natural killer (NK) cells are large granular lymphocytes that usually express the receptor IgG (FcgR) and the marker CD 56. NK cell functions, including natural killer cell cytotoxicity (NKC) and antibody-dependent cellular cytotoxicity (ADCC), are critically important parts of the host's early immune response to virus infections (Kohl S 2000). The effector mechanism is activated by interferon g and IL-2. NK cells produce and respond to cytokines that modulate their functions.
NK cells destroy infected and malignant cells. They recognize their targets in one of two ways. Like many other cells, they possess Fc receptors that bind IgG (FcgR). These receptors link cell, but this signal is normally overridden by an inhibitory signal sent by the killer-inhibitory receptor on recognition of MHC class I molecules.
Although all nucleated cells normally express MHC class I molecules on their surface, they can sometime lose this ability. This loss may occur as a result of either microbial interference with the expression mechanism - for example, after herpes virus infection or malignant transformation. Therefore, cells that lack MHC class I surface molecules are in some way abnormal. This lack of MHC class I molecules means that there are no NK cells to IgG-coated target cells, which they kill by a process called antibody-dependent cellular cytotoxicity (ADCC). The second system of recognition that is characteristic of NK cells relies on the killer-activating receptors and killer-inhibitory receptors of these cells. The killer-activating receptors recognize a number of different molecules present on the surface of molecular cells, whereas the killer-inhibitory receptors recognize MHC class I molecules, which are also usually present on all nucleated cells. If the killer-activating receptors are engaged, a "kill" instruction is issued to the natural killer inhibitory signal from the killer-inhibitory receptor, and the natural killer cell kills the abnormal target cell by inserting the pore-forming molecule into the membrane of the target cell and then injecting it with cytotoxic granzymes. This NK cell function is known as NK cell cytotoxicity (NKC).
Thus NK cells are the cells of innate response that recognize and then kill abnormal cells - for example, infected cells or tumour cells that lack cell-surface major histocompatibility complex (MHC) class I molecules.
NK cell activity has been found in human foetal liver cells at 8-11 week of gestation. NK lymphocytes are also derived from bone marrow precursors. Thymic processing is not necessary for NK-cell development, although NK cells have been found in thymus. Unlike T and B cells, NK cells do not rearrange antigen receptor genes during their development. After release from bone marrow NK cells enter the circulation or migrate to the spleen; there are very few NK cells in lymph nodes. In normal individuals, NK cells represent 10 % of lymphocytes.
Figure 2: A method used by natural killer cells to recognise normal cells that lack major-histocompatibility-complex class I surface molecules.
SUBPOPULATIONS OF T CELLS
T cells can be divided into two subpopulations based on the polypeptide chains constituting antigen receptor. The ab T cells, constituting the larger population (95%), posses a receptor comprising a hetrodimer of a and b T cell polypeptide chains. The T cell receptor is directed at the foreign antigen associated with MHC determinant. Activation of a b T cells requires recognition of either class I or class II MHC products on antigen presenting cells APCs). ab T cells can be divided by their surface expression of glycoproteins into CD4 and CD8 subpopulation. gd Tcells constitute approximately 5 % of circulating lymphoid T cells; their T cell receptor contains a heterodimer of g and d chains. Activation of g and d T cells does not require recognition of eitheir the class I or class II MHC products of APCs.
g
d T
cells
g d T cells have excited interest as a potential intermediary between nonspecific inflammatory cells and specific immune effector cells. They constitute approximately 5% of T cells in circulation and in lymphoid organs. g d T cells are not class I or class II MHC restricted and appear to target broadly cross-reactive human serum proteins (HSPs). Therefore, they may function in the initial or innate response to microbes and possibly in the pathogenesis of autoimmune diseases. gd T cells express cytokines and posses cytotoxic function. Their relative role in infection and immunity awaits definition.
MAJOR POPULATIONS OF B
CELLS: B1 AND B2 CELLS
B lymphocytes or B cells form one of the principal limbs of the immune system. The B cell division is responsible for the expression of humoral immunity - production of immunoglobulins - as opposed to expression of cell-mediated immunity by T cells.
The B cells that develop earliest during ontogeny are referred to as B1 cells. Most B cells express CD5, an adhesion and signalling cell-surface molecule. They are the source of the so-called natural antibodies, which are IgM antibodies and are frequently polyreactive (i.e. they recognize several different antigens, often including common pathogens). In most cases, natural antibodies have low affinity. They may be self-renewing (Youinou P, Jamin C, Lydiard PM 1999).
Most B cells lack the CD5 molecule, and because they develop slightly later in ontogeny, they are referred to as B2 cells. They are the chief population of B lymphocytes. They arise from stem cells in the bone marrow, do not express CD5, and secrete highly specific antibody within the secondary lymphoid tissues.
SUPERANTIGENS
Some bacterial exotoxins act as superantigens, which can induce a potent T cell proliferative response by combining with MHC class II molecules at a site distinct from the peptide-binding groove to form ligands that stimulate T cells via particular Vb chains of the T cell receptor. Because many T cells may carry the same Vb chain, superantigens react with more than 1/50 T cells whereas a conventional peptide antigen reacts with 1/10 4 to 1/10 6 T cells (Figure 3A).
Superantigen bacterial exotoxins include those produced by
staphylococci (e.g. toxins causing food poisoning such as enterotoxins A, B,
C1-3, D and E, toxic shock syndrome and the scalded skin syndrome involving
exfoliating toxins A and B), by group A streptococci (pyrogenic exotoxins A, B,
C and D), and by Clostridium perfringens and Yersinia enterocolitica (enterotoxins)
and Mycoplasma arthritidis.
The ability of bacterial exotoxins to activate large numbers of T cells with consequent release of cytokines could explain their pathogenic effects and the clinical syndromes they produce; for example, experimental staphylococcal enterotoxin shock depends on superantigen-induced release of TNF mediated via T cells. It seems clear that superantigens are another example of microbial pathogens evolving mechanisms to subvert the immune response.
A superantigen effect has also been demonstrated recently in Kawasaki's disease, a condition of childhood in which there is blood vessel inflammation (Meissner HC, Leung DYM 2000).
Certain viruses e.g. mouse mammary tumour virus (a retrovirus) can act as superantigens. The timing of interaction with superantigen is critical to the outcome: retroviral superantigens encountered during neonatal life caused the deletion, rather than expansion, of certain Vb-expressing T cells.
Superantigens versus
conventional antigens
Superantigens differ from conventional antigens in a number of important ways. Characteristics of an immune response induced by a superantigen include polyclonal B cell activation (in contrast to monoclonal activation), extensive proinflammatory production and changes in the number of circulating T lymphocytes which bear a specific surface receptor (specifically, Vb-restricted T cells). Superantigens cause extensive T cell proliferation and cytokine secretion after direct binding to major histocompatibility complex (MHC) class II proteins that reside on the surface of the antigen-presenting cell. A traditional protein antigen elicits an immune response only after ingestion by an antigen-presenting cell. Peptides from those antigens are expressed on the surface of the cell within a specific antigen-binding groove formed by MHC class II molecules. Only a limited number of lymphocytes respond to a conventional, processed antigen, typically less than 1 cell per 10,000 lymphocytes. In contrast, superantigens bind to MHC class II molecules on the surface of the antigen-presenting cell without ingestion and at a site outside the classical binding groove. The MHC-bound superantigen interacts with a T cell receptor (TCR) by means of a variable portion of the b-chain. All T cells possessing a specific sequence on the TCR receptor (Vb 2+ T cells) are activated by the MHC superantigen complex, and this may represent as many as 20 % of circulating lymphocytes. The result is release of unusually large amounts of cytokines from activated T cells (hence the name superantigen). Cytokines then mediate the disease process.
IMMUNIZATIONS
Immunization Programmes and
Herd Immunity
"Herd-Immunity" is the basis on which all national immunization programmes are designed. It is the concept that not everybody in a population has to be immuninized to protect everyone in that population. As long as a sufficient number of children are immunized against each disease for which there is a vaccine, protection against that disease will be conferred on everybody. The percent of the population that must however be immunized depends on three factors: the infectivity of the disease, the vulnerability of the population, and environmental factors (Begg NT, Gay NJ 1997). In order to confer 100% protection in any community disease such as measles, which is highly infectious, will require a larger number of children to be immunized against it than, for example, mumps which is less contagious. A crowded inner city community will need a higher proportion of all vulnerable children to be immunized than a sparsely populated rural area. On average, to achieve 100% protection against measles in the UK the uptake of immunization must be about 95%: whereas in India uptake has to reach about 99% to reach the same level of protection. For meningitis it is apparent that there are more cases of the disease in winter than in summer. This suggests that environmental factors, and possibly cofactors such as the influenza virus, play a part in the generation of a new case of meningitis.
The "effective reproduction rate" (R) is the average number of infections that each case generates. If R is 1 then a state of equilibrium exists. If R is less than 1 then the disease in question will eventually become extinct. For measles R is about 16. This means that each case of measles can expect to generate about 16 new cases in a susceptible population. The aim of Herd immunity is to reduce R to less 1 for each disease thus stopping the disease from propagating in the community.
Over time, as the proportion of children who are immunized in a population increases, the number of new cases of a disease should drop. If however, enough parents decide not to have their children vaccinated, more cases will start to appear and then the entire population is put at risk. Successful Herd community relies on health workers and patients' co-operation to immunize sufficient numbers of children.
Impact
of Hib vaccine on Haemophilus Influenzae infection
Haemophilus influenzae isolates are classified into 6 antigenically distinct capsular types (a through f). Most cases of invasive diseases in children, before the introduction of H. influenzae type b (Hib) conjugated vaccination were caused by type b in the US.
H. influenzae type b (Hib) causes sinusitis, pneumonia, epiglottis and most commonly otitis media. Epiglottis is an important manifestation of H. influenzae, type b in children between 2 to 4 years. Epiglottis is characterized by cellulitis and swelling of the supraglottic tissues. It can rapidly progress to compete obstruction of the airway and death. Hence it represents a life threatening paediatric emergency. Invasion of the bloodstream can produce complications like meningitis and endocarditis. Pneumonia, meningitis and endocarditis carry a high mortality. Before the introduction of effective vaccine, Hib was the most common cause of bacterial meningitis in children in the United States.
Since 1988, when Hib conjugate vaccines were introduced, the incidence of Hib disease in infants and young children has declined by 99%. As a result of this success, the US Public Health Service has targeted Hib disease in children younger than 5 years of age for elimination in the USA. Invasive Hib disease occurs now in the US primarily in underimmunized children and among infants too young to have completed the primary immunization series.
The recent introduction of conjugate Streptococcus pneumoniae
vaccine will further reduce the invasive bacterial disease in the United
States.
The artificial immunization against common important infections has greatly improved the health of infants and young children. Smallpox has been eradicated. Tetanus, diphtheria, pertussis, Haemophilus influenzae Group b streptococcus pneumoniae, poliovirus, hepatitis virus B, measles, rubella, mumps, and varicella infections are effectively prevented. The development of other safe, effective immunizing agents are of particular importance as more antibiotic-resistant bacterial pathogens emerge and as we are exposed to microbial pathogens that once were confined to comparatively isolated regions of the world.
Rotavirus Vaccine: The
Future
The future of a potentially lifesaving vaccine for developing countries has been imperilled by its recent withdrawal from the United States market. In August 1995, tetravalent rhesus rotavirus vaccine was licensed for routine vaccination in the United States on the basis of randomised controlled trials there and in Finland. The trials showed that the vaccine had an efficacy of 49-68% in preventing rotavirus diarrhoea overall and importantly, 69-91% efficacy in preventing severe disease.
In July 1999, the US Center for Disease Control and Prevention reported a clustering of cases of intussusception in the weeks after vaccination with tetravalent rhesus rotavirus vaccine, representing an additional risk of 1 in 10,000 for this complication. On the basis of this finding they recommended postponing administration of tetravalent rhesus rotavirus vaccine to children. This leaves researchers with a moral quandary: should randomized controlled trials of tetravalent rhesus rotavirus vaccine proceed in developing countries?
Weijer (2000) for the sake of argument, advances the worst assumption of a case scenario of 0.025% fatality rate from intussuception in developing countries, widespread use of tetravalent rhesus rotavirus vaccine could then cause 2000-3000 deaths a year. On the other hand, developing countries have a totally different scenario where about three million children die of diarrhoea annually despite efforts to prevent death with programmes of oral rehydration therapy. Of these 600,000 are caused by rotavirus diarrhoea, and if the current vaccine prevents 80% of these deaths, he argues, then by the time the new vaccine is developed and used, 1.4-3.2 million preventable deaths would have occurred.
Intravenous Immune Globulin
in Immunodeficiency Diseases
Intravenous Immune Globulin (IVIG) has been used in the antibody deficiency disorders since 1991 (Buckly RH, Schiff RI 1991) and has largely replaced intramuscular administration of immune globulin. Replacement therapy with IVIG results in clinical improvement and decreases the incidence of irreversible organ damage (e.g. bronchiactasis) in patients who have selected antibody deficiencies. Currently IVIG is indicated for all cases of X-linked agammaglobulinemia, hyper IgM syndrome and common variable immmunodeficiency. It also is used in many combined immmunodeficiency syndromes, such as severe combined immunodificiency disease.
IVIG consists of sterile solutions of pooled polyspecific human IgG with concentrations of measles, diptheria, polio, cytomegalovirus, and hepatitis antibodies. It is available either as a lypholized powder or a liquid at concentration of 5%, 10%, or 12%. IVIG is usually given every 3 to 4 weeks. It is typically given over 2 to 6 hours depending on the dose and the patient's clinical status.
IVIG has proven effective in the management of many paediatric diseases that have an immunologic component. In addition to its role in treatment of antibody deficiency syndromes, IVIG can help to prevent the serious cardiac consequences of Kawasaki disease, and it shortens the course of acute idiopathic thrombocytopenic purpura. In children who have a polyclonal gammopathy, with elevated levels of dysfunctional immunoglobulins, IVIG can reduce the frequency of serious bacterial infections (Schuval SJ 2000).
REFERENCES
The Skin as an Immune System
Elias PE, Feingold KR (1999) Skin as an organ of protection in Fitzpadrics-Dermatology in General Medicine, 5th edn, McGraw Hill, New York.
Jullien D, Moldin RL, Nicolas JF (1999) The skin immune system in Euvard S, Kanitakis J, Claudy A (editors) Skin disease after organ transplantation. John Libbey, Eurotext, Paris, France.
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Shroder JM (1995) Cytokine networks in the skin. J Invest Dermatol 105: 205.
Recent Insight into Natural Killer Cells
Kohl S (1999) Human neonatal natural killer cell cytotoxicity function. Pediatr Infect Dis 18: 635-637.
Major Population of B Cells: B1 and B2 Cells
Youinou P, Januin C Lydyard PM (1999) CD5 expression in human B cells populations. Immunol Today 20: 312-316.
Superantigens
Meissner KC, Leung DYM (2000) Superantigens, conventional antigens and the etiology of Kawasaki syndrome. Pediar Infect Dis 19:91-94.
Immunizations and Herd Immunity
Begg NT, Gray NJ (1997) Theory of infectious disease transmission and herd immunity in Balows A, Sussaman M (eds) Topley and Wilson's Microbiology and Microbial Infections. 9th edn vol 3, Edward Arnold, London.
Rotavirus:
The Future
Weiger C (2000) The future of research into rotavirus vaccine. Br Med J 321: 525-526.
Intravenous
Immune Globulin
Buckley RH, Schiff RI (1991) The use of Intravenous globulin in immunodeficiency disease. N Engl J Med 325: 110-117.
Schuval SJ (2000) Treatment of antibody deficiency syndromes. Pediatrics in Review 21: 358-369.