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Overview of the Immune System

By

Peter J. Delves

, PhD, University College London, London, UK

Last full review/revision Sep 2021| Content last modified Sep 2021
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The immune system distinguishes self from nonself and eliminates potentially harmful nonself molecules and cells from the body. The immune system also has the capacity to recognize and destroy abnormal cells that derive from host tissues. Any molecule capable of being recognized by the immune system is considered an antigen (Ag).

The skin, cornea, and mucosa of the respiratory, gastrointestinal, and genitourinary tracts form a physical barrier that is the body's first line of defense. Some of these barriers also have active immune functions:

  • Outer, keratinized epidermis: Keratinocytes in the skin secrete antimicrobial peptides (defensins), and sebaceous and sweat glands secrete microbe-inhibiting substances (eg, lactic acid, fatty acids). Also, many immune cells (eg, mast cells, intraepithelial lymphocytes, antigen-sampling Langerhans cells) reside in the skin.

  • Cornea: Neutrophils reach the cornea through vessels at the limbus and kill microbes by phagocytosis.

  • Mucosa of the respiratory, gastrointestinal, and genitourinary tracts: The mucus contains antimicrobial substances, such as lysozyme, lactoferrin, and secretory immunoglobulin (Ig) A antibody (SIgA).

Breaching of anatomic barriers can trigger 2 types of immune response:

  • Innate

  • Acquired

Innate immunity

Innate (natural) immunity does not require prior exposure to an antigen (ie, immunologic memory) to be fully effective. Thus, it can respond immediately to an invader. Innate immunity recognizes mainly molecular patterns that are broadly distributed rather than an antigen specific to one organism or cell.

Components include

  • Phagocytic cells (eg, neutrophils, monocytes, macrophages)

  • Polymorphonuclear leukocytes

  • Innate lymphoid cells (eg, natural killer [NK] cells)

Acquired immunity

Acquired (adaptive) immunity requires prior exposure to an antigen to be fully effective and takes time to develop after the initial encounter with a new invader. Thereafter, response is quick. The system remembers past exposures and is antigen-specific.

Components include

  • B cells

  • T cells

Acquired immunity includes

Immune Response

Successful immune defense requires activation, regulation, and resolution of the immune response.

Activation

The cells of the immune system are activated when a foreign antigen (Ag) is recognized by cell surface receptors. These cell surface receptors may be

  • Broadly specific (eg, pattern-recognition receptors such as Toll-like, mannose, and scavenger receptors on dendritic and other cells)

  • Highly specific (antibodies expressed on B cells or T-cell receptors expressed on T cells)

Broadly specific receptors recognize common microbial pathogen-associated molecular patterns such as gram-negative lipopolysaccharide, gram-positive peptidoglycans, bacterial flagellin, unmethylated cytosine-guanosine dinucleotides (CpG motifs), and viral double-stranded RNA. These receptors can also recognize molecules that are produced by stressed or infected human cells (called damage-associated molecular patterns).

Activation may also occur when antibody-antigen and complement-microorganism complexes bind to surface receptors for the crystallizable fragment (Fc) region of IgG (Fc-gamma R) and for C3b and iC3b.

Once recognized, an antigen, antigen-antibody complex, or complement-microorganism complex is internalized. Most microorganisms are killed after they are phagocytosed, but others inhibit the phagocyte’s intracellular killing ability (eg, mycobacteria that have been engulfed by a macrophage inhibit that cell's killing ability). In such cases, T cell–derived cytokines, particularly interferon-gamma (IFN-gamma), stimulate the phagocyte to produce more lytic enzymes and other microbicidal products and thus enhance its ability to kill or sequester the microorganism.

Unless antigen is rapidly phagocytosed and entirely degraded (an uncommon event), the acquired immune response is recruited via recognition of antigen by the highly specific receptors on the surface of B and T cells. This response begins in

  • The spleen for circulating antigen

  • Regional lymph nodes for tissue antigen

  • Mucosa-associated lymphoid tissues (eg, tonsils, adenoids, Peyer patches) for mucosal antigen

For example, Langerhans dendritic cells in the skin phagocytose antigen and migrate to local lymph nodes; there, peptides derived from the antigen are expressed on the surface of dendritic cells within class II major histocompatibility complex (MHC) molecules Human Leukocyte Antigen (HLA) System The human leukocyte antigen (HLA) system (the major histocompatibility complex [MHC] in humans) is an important part of the immune system and is controlled by genes located on chromosome 6.... read more , which present the peptide to CD4 helper T (Th) cells. When the Th cell engages the MHC-peptide complex and receives various costimulatory signals (which can be inhibited by some immunosuppressive drugs), it is activated to express receptors for the cytokine interleukin (IL)-2 and secretes several cytokines. Each subset of Th cells secretes different combinations of substances and thus effects different immune responses.

Class II MHC molecules typically present peptides derived from extracellular (exogenous) antigen (eg, from many bacteria) to CD4 Th cells; in contrast, class I MHC molecules typically present peptides derived from intracellular (endogenous) antigens (eg, from viruses) to CD8 cytotoxic T cells. The activated cytotoxic T cell then kills the infected cell.

Regulation

The immune response must be regulated to prevent overwhelming damage to the host (eg, anaphylaxis Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more , cytokine storm Pathophysiology Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more , cytokine release syndrome, and widespread tissue destruction). Regulatory T cells (most of which express Foxp3 transcription factor) help control the immune response via secretion of immunosuppressive cytokines, such as IL-10 and transforming growth factor-beta (TGF-beta), or via cell contact dependent mechanisms.

These regulatory cells help prevent autoimmune responses and probably help resolve ongoing responses to nonself antigen.

Resolution

The immune response resolves when antigen is sequestered or eliminated from the body. Without stimulation by antigen, cytokine secretion ceases, and activated cytotoxic T cells undergo apoptosis. Apoptosis tags a cell for immediate phagocytosis, which prevents spillage of the cellular contents and development of subsequent inflammation. T and B cells that have differentiated into memory cells are spared this fate.

Geriatrics Essentials

With aging, the immune system becomes less effective in the following ways:

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