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, corneas, 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.
Corneas: Tears contain defensins. Macrophages and dendritic cells reside in the corneas and other immune cells, including T cells and phagocytic neutrophils, are recruited through the limbal vasculature during infection.
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
Many molecular components (eg, complement, cytokines, acute phase reactants) participate in both innate and acquired immunity.
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 uses pattern recognition receptors (PRRs) to detect foreign pathogen-associated molecular patterns (PAMPs) and host damage-associated molecular patterns (DAMPs).
Components include
Phagocytic cells (eg, neutrophils, monocytes, macrophages)
Polymorphonuclear leukocytes (in addition to phagocytic neutrophils, including eosinophils and basophils)
Innate lymphoid cells (eg, natural killer [NK] cells)
Phagocytic cells (neutrophils in blood and tissues, monocytes in blood, macrophages in tissues) ingest and destroy invading antigens. Attack by phagocytic cells can be facilitated when antigens are coated with antibody (Ab), which is produced as part of acquired immunity, or when complement proteins opsonize antigens.
Polymorphonuclear leukocytes (neutrophils, eosinophils, basophils) and mononuclear cells (monocytes, macrophages, mast cells) release inflammatory mediators.
Natural killer cells kill virus-infected cells and some tumor 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
Humoral immunity: Derived from B-cell responses (B cells develop into plasma cells, which secrete soluble antigen-specific antibody)
Cell-mediated immunity: Derived from certain T-cell responses
B cells and T cells reach maturity within the primary lymphoid tissues. B cells mature in the bone marrow, and T cells mature in the thymus. Mature B cells and T cells subsequently work together to destroy invaders. Tissue-based antigen-presenting cells are needed to present antigens to most types of T cell.
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 specific for
Structures (PAMPs) that are associated with a number of different pathogens (eg, recognition by PRRs such as Toll-like, mannose, and scavenger receptors on dendritic and other cells)
Structures that are specifically associated with particular pathogens (recognition by transmembrane antibodies expressed on B cells or by T-cell receptors expressed on T cells)
PRRs recognize common microbial PAMPs 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 (DAMPs) that are produced by stressed or infected human cells.
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 phagocytosed. 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 cells and T cells. This response begins in the secondary lymphoid tissues:
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. In the lymph nodes, peptides derived from the antigen are expressed on the surface of dendritic cells within class II major histocompatibility complex (MHC) molecules, 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 medications), 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.
Some of the Th cells become specialized as T follicular helper (Tfh) cells, which migrate into B cell areas of the secondary lymphoid tissues. During an active immune response, structures called germinal centers develop within secondary lymphoid tissues where the Tfh cells assist in B-cell activation, proliferation, antibody class switching, affinity maturation of the antibody response, and B-cell differentiation in memory B cells and into the precursors of the antibody-secreting plasma cells. Also within the germinal centers are follicular dendritic cells (an entirely different cell type to conventional dendritic cells), which present intact antigen (in antigen-antibody complexes) to the B cell.
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, cytokine storm, 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 cells and B cells that have differentiated into memory cells are spared this fate.
Geriatrics Essentials: Immune System
With aging, the immune system becomes less effective in the following ways:
The immune system becomes less able to distinguish self from nonself, making the development of autoantibodies and autoimmune disorders more common.
Macrophages destroy bacteria, cancer cells, and other antigens more slowly, possibly contributing to the increased incidence of cancer among older adults.
T cells respond less quickly to antigens.
There are fewer lymphocytes that can respond to new antigens.
The aging body produces less complement in response to bacterial infections.
Although overall antibody concentration does not decline significantly, the binding affinity of antibody to antigen is decreased, possibly contributing to the increased incidence of pneumonia, influenza, infective endocarditis, and tetanus and the increased risk of death due to these disorders among older adults. These changes may also partly explain why vaccines are less effective in older adults.
