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 (see Tumor Immunology). Any molecule capable of being recognized by the immune system is considered an antigen (Ag).

The skin, cornea, and mucosa of the respiratory, GI, and GU 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, Ag-sampling Langerhans cells) reside in the skin.
• Mucosa of the respiratory, GI, and GU tracts: The mucus contains antimicrobial substances, such as lysozyme, lactoferrin, and secretory IgA antibody (SIgA).

Breaching of anatomic barriers can trigger 2 types of immune response: innate and acquired. Many molecular components (eg, complement, cytokines, acute phase proteins) participate in both innate and acquired immunity.

Innate immunity

Innate (natural) immunity does not require prior exposure to an Ag (ie, memory) to be effective. Thus, it can respond immediately to an invader. It recognizes mainly Ag molecules that are broadly distributed rather than specific to one organism or cell. Components include

• Phagocytic cells
• Ag-presenting cells
• Natural killer (NK) cells
• Polymorphonuclear leukocytes

Phagocytic cells (neutrophils and monocytes in blood, macrophages and dendritic cells in tissues) ingest and destroy invading Ags. Attack by phagocytic cells can be facilitated when Ags are coated with antibody (Ab), which is produced as part of acquired immunity, or when complement proteins (part of the less specific innate defense system) opsonize Ags. Ag-presenting cells (macrophages, dendritic cells) present fragments of ingested Ags to T cells (which are part of acquired immunity). Natural killer cells kill virus-infected cells and some tumor cells. Certain polymorphonuclear leukocytes (eosinophils, basophils, mast cells) and mononuclear cells release inflammatory mediators.

Acquired immunity

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

• T cells
• B cells

Acquired immunity derived from certain T-cell responses is called cell-mediated immunity. Immunity derived from B-cell responses is called humoral immunity because B cells secrete soluble Ag-specific Ab. B cells and T cells work together to destroy invaders. Some of these cells do not directly destroy invaders but instead enable other WBCs to recognize and destroy invaders.

Immune Response

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

Activation

The immune system is activated when a foreign Ag is recognized by circulating Abs or cell surface receptors. These receptors may be highly specific (Ab expressed on B cells or T-cell receptors) or broadly specific (eg, pattern-recognition receptors such as Toll-like, mannose, and scavenger receptors on dendritic and other cells). Broadly specific receptors recognize common microbial pathogen-associated molecular patterns in ligands, such as gram-negative lipopolysaccharide, gram-positive peptidoglycans, bacterial flagellin, unmethylated cytosine-guanosine dinucleotides (CpG motifs), and viral double-stranded RNA. Activation may also occur when Ab-Ag and complement-microorganism complexes bind to surface receptors for the crystallizable fragment (Fc) region of IgG (FcγR) and for C3b and iC3b.

Once recognized, an Ag, Ag-Ab complex, or complement-microorganism complex is phagocytosed. Most microorganisms are killed after they are phagocytosed, but others (eg, mycobacteria) inhibit the phagocyte's ability to kill them once they are engulfed. In such cases, T cell–derived cytokines, particularly interferon-γ (IFN-γ), stimulate the phagocyte to produce lytic enzymes and other microbicidal macrophage products, which kill or sequester the microorganism.

Unless Ag is rapidly phagocytosed and entirely degraded (an uncommon event), the acquired immune response is recruited. This response begins in the spleen for circulating Ag, in regional lymph nodes for tissue Ag, and in mucosa-associated lymphoid tissues (eg, tonsils, adenoids, Peyer patches) for mucosal Ag. For example, Langerhans dendritic cells in the skin phagocytose Ag and migrate to local lymph nodes; there, peptides derived from the Ag are expressed on the cell surface within class II major histocompatibility complex (MHC) molecules, which present the peptide to CD4 helper T (T_H) cells. When the T_H cell engages the MHC-peptide complex and receives various costimulatory signals, it is activated to express receptors for the cytokine IL-2 and secretes several cytokines. Each subset of T_H cells secretes different combinations of substances, and thus effect different immune responses (see Biology of the Immune System: T cells).

Class II MHC molecules typically present peptides derived from extracellular (exogenous) Ag (eg, from many bacteria) to CD4 T_H cells; in contrast, class I MHC molecules typically present peptides derived from intracellular (endogenous) Ag (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, 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-β (TGF-β), or via a poorly defined cell contact mechanism. These regulatory cells help prevent autoimmune responses and probably help resolve ongoing responses to nonself Ag.

Resolution

The immune response resolves when Ag is sequestered or eliminated from the body. Without stimulation by Ag, 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:

• The immune system becomes less able to distinguish self from nonself, making autoimmune disorders more common.
• Macrophages destroy bacteria, cancer cells, and other Ag more slowly, possibly contributing to the increased incidence of cancer among the elderly.
• T cells respond less quickly to Ag.
• There are fewer lymphocytes that can respond to new Ag.
• The aging body produces less complement in response to bacterial infections.
• Less Ab is produced in response to Ag, and Ab is less able to attach to Ag, possibly contributing to the increased incidence of pneumonia, influenza, infectious endocarditis, and tetanus and the increased risk of death due to these disorders among the elderly. These changes may also partly explain why vaccines are less effective in the elderly.

Last full review/revision November 2012 by Peter J. Delves, PhD