Host defence mechanisms and immunodeficiency disorders

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Chapter 59 Host defence mechanisms and immunodeficiency disorders

Steve Wesselingh, Martyn AH. French

There is a coordinated immunological response to infection involving both cellular and humoral components. The outcome of an infection will be determined by the balance between the body’s ability to eliminate invading microorganisms and the microorganism’s virulence. Humans have diverse host defence mechanisms to protect the different anatomical compartments of the body from a great variety of microorganisms (Table 59.1). There are many ways in which the immune system can be defective, leading to an increased propensity to infections. The immune response also needs to be controlled to avoid inappropriate and excessive activation, which may damage the host. A certain degree of host damage is inevitable during the response to infection, particularly if there is systemic activation resulting in disseminated intravascular coagulation (DIC) and an excessive inflammatory response.

Table 59.1 Host defence mechanisms

Physical barriers

Skin and mucosal surfaces

Cilia

Fever

Lysozyme

Lactoferrin

Acute-phase proteins, e.g. C-reactive protein

Fibronectin

Immune system, including secondary mediators

Other mediators of inflammation

Kinins

Vasoactive amines

Coagulation system

INNATE IMMUNE RESPONSES

The immune system is capable of reacting to microorganisms without having been previously exposed to antigens from those microorganisms. This innate immune system consists of plasma proteins, including alternative-pathway components of the complement system and mannose-binding lectin (MBL), a subset of lymphocytes with cytotoxic activity (natural killer or NK cells), and some macrophage functions. Innate immune responses provide a first line of defence against many pathogenic microorganisms.

ACUTE-PHASE REACTION

The acute-phase reaction is a response of the haematopoietic and hepatic systems, involving at least 20 plasma proteins and the cellular components of the blood. The reaction occurs within hours of acute physical stress or infection. The functions of many of these acute-phase proteins remains unclear, but teleologically, they should be assumed to be beneficial to the patient. The falls in haemoglobin, serum iron and albumin are all normal in the acute-phase reaction. Most of the proteins are inflammatory mediators or inhibitors of transport proteins. Fibrinogen, the bulk protein of the coagulation system, is one of the plasma proteins to show the greatest rise in the acute-phase reaction, and is responsible for the elevation in the erythrocyte sedimentation rate. The fall in albumin is due to redistribution and decreased synthesis and generally does not require supplementation.

THE ADAPTIVE IMMUNE SYSTEM

Adaptive immune responses are characterised by specificity, memory, amplification and diversity. The specificity of an immune response against a particular antigenic component of a microorganism, and the memory which results in a prompt response on subsequent exposures, is determined by lymphocytes and antigen receptors on their surface. Amplification and diversity of immune responses are regulated by cytokines, which are secreted by lymphocytes and other cells, and through the effects of various lymphocyte surface molecules, including adhesion molecules and co-stimulatory molecules. Cytokines have various activities, the most important of which are cell activation (e.g. interferon-gamma (IFN-γ)), regulation of immune responses (e.g. interleukin (IL)-10) and proinflammatory effects (e.g. tumour necrosis factor (TNF)) and lymphotoxins).

ANTIGEN PRESENTATION

The most important events in the initiation of an immune response are the processing and presentation of fragments of the microorganism in a form which makes the fragments antigenic to lymphocytes. Major histocompatibility complex (MHC) class I (human leukocyte antigen (HLA)-A, B, C) and class II (HLA-DR, DP, DQ) molecules are the major cell-surface antigen presentation molecules. These molecules also determine the nature of the subsequent response against the antigen. Class I MHC molecules are present on most nucleated cells, and present processed endogenous peptides (such as fragments of viruses) to the antigen receptor (T-cell receptor; TcR) of T cells expressing CD8 molecules. Class II MHC molecules present antigenic fragments of microorganisms which are exogenous to cells and have been taken into the cell by phagocytosis, in the case of macrophages and monocytes, or by binding to antigen-specific surface immunoglobulins (the B-cell antigen receptor), in the case of B cells. Antigens presented on class II MHC molecules bind to TcRs on CD4+ T cells.

T CELLS AND B CELLS

CD8+ T cells have a cytotoxic effect on cells expressing class I MHC-associated viral antigens, resulting in the death of the cell and inhibition of viral replication. Antigen-induced stimulation of CD4+ T cells results in activation of the T cell and the expression of cell-surface molecules and secretion of cytokines with immunoregulatory effects. These immunoregulatory molecules augment the functions of many other cells, including B cells, T cells and macrophages (T-cell help). A response to an antigen directed by CD4+ T cells may also elicit macrophage activation and killing of the microorganism expressing that antigen. Activation of macrophages by CD4+ T cells is critically dependent on the production of IFN-γ.

The activation and proliferation of T cells occur under the influence of cytokines and other regulatory molecules, including co-stimulatory molecules such as the ligand of the B-cell membrane molecule CD40 (CD40L). Proliferating B cells differentiate into plasma cells, which secrete immunoglobulins with antibody activity against the initiating antigen. Nine isotypes of immunoglobulin can be produced, each of which has a different function.

IMMUNOGLOBULINS AND ANTIBODIES

Immunoglobulin M (IgM) is a large pentameric molecule, which is particularly effective as a bacterial agglutinator and activator of the complement system, and has its major effect within the circulation. IgA₁ and IgA₂ are produced at secretory surfaces, such as the mucosa of the gut and respiratory tract, and also in the breast, where IgA is a major constituent of the colostrum and provides secretory antibody to the gut of the neonate. IgE antibodies are also produced at mucosal surfaces where they form an important part of the immune response against parasitic infections. Antibodies of the IgG₁ and IgG₃ subclass are particularly effective at activating the complement system and binding to Fc receptors on phagocytic cells. IgG₂ antibodies are mainly active against polysaccharide antigens, such as those present in bacterial cell walls. The functions of IgG₄ antibodies are unclear.

SECONDARY ANTIBODY FUNCTION

The elimination of a microorganism by antibodies usually requires the activation of a secondary effector mechanism, of which there are several. Antibodies complexed with antigens activate the complement system through the classical pathway. The complement system may also be activated directly by components of microorganisms through the alternative pathway or MBL pathway. Activation of the complement system results in the generation of biologically active molecules, such as C3b, which is an important opsonin, and the activation of the membrane attack complex (MAC), which lyses bacterial cell walls. Like C3b, antibodies of the IgM, IgG₁ and IgG₃ isotype are also important opsonins. These molecules, when bound to the surface of a microorganism, facilitate their opsonisation and phagocytosis. These effects of complement and antibody are mediated through complement receptors (CRs) and receptors for the Fc portion of the immunoglobulin molecules (Fc receptors) on the surface of phagocytic cells such as neutrophils and macrophages.

DIVERSITY OF IMMUNE RESPONSES

The type of immune response produced against a microorganism varies according to the nature of the infecting organism. Thus, virus-infected cells elicit a cytotoxic CD8+ T-cell response; intracellular pathogens such as mycobacteria and protozoa elicit a CD4+ T-cell response, which results in macrophage activation; encapsulated bacteria elicit an opsonising antibody response; and some bacteria such as Neisseria spp. elicit a complement-activating antibody response, which lyses the cell wall of the bacterium. The nature of the immune response is regulated by cytokines, which provide T-cell help (Th) in the course of an immune response. Thus, IL-2, IL-12 and IFN-γ production induces a predominantly cellular immune response (Th1), whereas the production of IL-4 and IL-13 induces a predominantly antibody-mediated immune response (Th2).

IMMUNE DEFECTS UNDERLYING IMMUNODEFICIENCY DISORDERS

Defects of the immune system may give rise to immunodeficiency disorders, which are generally of five types: antibody deficiency, complement deficiency, cellular immunodeficiency, combined immunodeficiency (T cells, B cells and NK cells) and phagocyte dysfunction.

ANTIBODY DEFICIENCY

A deficient systemic antibody response most commonly results in a lack of opsonising antibody, and a propensity to infections with encapsulated bacteria such as pneumococci or Haemophilus influenzae. Recurrent respiratory tract infections including sinusitis are therefore the most common complication of this type of immune defect. Chronic echovirus infections of the nervous system and infection with some mycoplasmas may also occur in patients with severe primary immunoglobulin deficiency (agammaglobulinaemia).

Deficient secretory antibody responses are common in patients with IgA deficiency, but most affected individuals are able to produce compensatory secretory IgM or IgG antibody responses and do not suffer from infections.

CELLULAR IMMUNODEFICIENCY

Impairment of cell-mediated immune responses leads to an increased propensity to infection with microorganisms which are normally controlled by cellular immune responses (Table 59.2). These microorganisms are often pathogens that replicate intracellularly (intracellular pathogens) and cause persistent (latent) infections that reactivate when the cellular immune response against them becomes ineffective.

Table 59.2 Microorganisms that most commonly cause disease in patients with cellular immunodeficiency

Mycobacteria	Mycobacterium tuberculosis
Mycobacteria	Non-tuberculous mycobacteria
Bacteria	Salmonella spp.
	Shigella spp.
	Listeria monocytogenes
Fungi and yeasts	Candida spp. (mucosal infections)
	Pneumocystis jiroveci
	Cryptococci
	Aspergillus spp.
Protozoa	Toxoplasma gondii
Protozoa	Cryptosporidia
Viruses	Herpes simplex viruses
	Cytomegalovirus
	Varicella-zoster virus
	Epstein–Barr virus
	Molluscum contagiosum virus
	JC virus (cause of progressive multifocal leukoencephalopathy)

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