By Levi Clancy for Student Reader on
The immune system has evolved to deal with invasion by microbial pathogens. The main task of the immune system is to distinguish self from non-self.
The immune system must not attack and destroy self, but it must eliminate whole organisms (such as bacteria and fungi) as well as intracellular pathogens (such as viruses). Connected by blood and lymph, the immune system is a concert of cells, tissues and organs working together to protect their host. These cells, tissues and organs communicate via direct surface interaction and via chemical communication.
In chemical communication, cells release cytokines that flow through blood and lymph to initiate cells elsewhere throughout the body. The immune system is broken into two main components: innate immunity and acquired immunity.
|Innate Immunity||Anatomic barriers|
|Evolutionarily older, innate immunity is a non-specific inherited defense system that provides a general response against all pathogens. Innate immune system cells discriminate between pathogens and self via cell surface receptors that recognize patterns. Innate immunity defends against pathogens by rapid responses coordinated through "innate" receptors that recognize a wide spectrum of conserved pathogenic components. Plants and many lower animals do not possess an adaptive immune system, and rely instead on their innate immunity.|
|Acquired Immunity||T Cells|
|Acquired immunity (aka adaptive immunity) first evolved in sharks and rays, and improved as the evolution progressed. Acquired immunity is adaptive and specific, meaning it is an immune response rather than a broad non-specific barrier. This response takes days to develop, and so is not effective at preventing an initial invasion, but it will normally prevent any subsequent infection, and also aids in clearing up longer-lasting infections. This immune response must not only determine self from non-self, but also distinguish various forms of non-self. For example, an effective immune response to a bacterial infection has no effect on a viral infection.|
Non-self structures are known as antigens and are the target of the immune response.
Antigens must be based on carbon and the atoms which bond to it (hydrogen, oxygen, nitrogen, phosphorous and sulfur). This means the immune response detects only bio-organic antigens, essentially limiting it to chemicals encoded or controlled by genes.
The immune response consists of B and T cells that detect subtle protein, carbohydrate, lipid and other structure differences to distinguish self from non-self microbes (and the kind of non-self microbe).
Antigen elimination is basically a three-step process: antigen recognition, antigen binding and antigen elimination. The result is obliteration of antigens and their corresponding foreign microbes. Antigen elimination involves B cells, T cells, macrophages and antibody.
Chemicals released during antigen elimination lead to inflammation. Inflammation includes: fever; vascular permeability; fluid build-up in tissues (edema); and even tissue damage, which initiates healing.
Innate immunity is a non-specific inherited defense system that provides a general response against all pathogens. Innate immunity provides the body's first protection against invaders (on the other hand, acquired immunity -- aka adaptive immunity -- responds to a persisting infection). Innate immunity stimulates adaptive immunity, influencing its expression to optimize its response against the specific types of invading microbes. Also, innate immunity is so effective that its mechanisms are often included in acquired immunity. Innate immunity consists of the following:
|Anatomic Barriers||Anatomic barriers (aka mechanical barriers) include: tight junctions of epithelial cells, forming a physical barrier between the host and the environment. Also, mucous membranes are sticky and trap organisms from entering the body.|
|Physiologic Barriers||Physiologic barriers (aka chemical barriers) include pH, soluble factors (peptides & enzymes), oxygen tension and even temperature. HCl keep the stomach and intestine at a low pH, and keratin keeps the epidermis acidic as well. Soluble factors include enzymes such as lysozyme (which is found in mucous and cleaves bacterial peptidoglycans), interferons (which have an antiviral effect and is produced by infected cells) and complement proteins (which initiate bacterial lysis upon contact with sialic acid). Also, there are broad-spectrum antibacterial defensins, which are cysteine-rich 29-34 amino acid peptides.|
|Endocytosis & Phagocytosis||Endocytosis is performed by all cells and delivers macromolecules to the endosome. Phagocytosis is performed by monocytes, macrophages and neutrophils. In phagocytosis, organisms are engulfed by a cell and then lysed within phagosomes. The receptor for phagocytosis binds to bacterial lipopolysaccharide.|
|Inflammatory Response||Inflammation is characterized by vasodilation, an increase in capillary permeability and an influx of phagocytes.|
Cells of the innate immune system recognize non-self antigens via pattern-recognition receptors. Pattern-recognition receptors are receptors on the cell surface that are encoded by the genome and can detect repetitive structures (or patterns) specific to pathogens. Important cells of the innate immune system include:
|Mast Cells||Mast cells secrete inflammatory substances.|
|Intraepithelial T Cells||Intraepithelial T cells express a non-adaptive range of antigen receptors.|
|CD5 B Cells||Also known as B1 Cells, CD5 B cells secrete complement-inducing antibodies with 48 hours of exposure to bacterial capsular polysaccharides. CD5 B cells are a bridge until the adaptive T cell response activates, but lack memory (unlike the T cell response).|
|Phagocytes||Macrophages and neutrophils are important phagocytes in innate immunity.|
When a phagocyte recognizes a pathogen, there are four important consequences: phagocytosis of the pathogen; cytokine secretion by the phagocyte; induction of co-stimulatory molecules; and, in macrophages and dendritic cells, antigen uptake, processing and presentation. Thus, phagocytes play an important role in initiating the immune response. The steps of the immune system can be broken into the following:
|Physiologic Barrier||The first-line defense includes barriers to infection, such as skin and mucus coating of the gut and airways, physically preventing the interaction between the host and the pathogen. Pathogens, which penetrate these barriers, encounter constitutively-expressed anti-microbial molecules (eg. lysozyme) that restrict the infection. In addition to the usual defense, the stomach secretes gastric acid which, apart from aiding digestive enzymes in the stomach to work on food, prevents bacterial colonization.|
|Phagocytic Cells||The second-line defense includes phagocytic cells (macrophages and neutrophil granulocytes) that can phagocytose (engulf) foreign substances. Phagocytic cells are attracted to microorganisms by means of chemotactic chemicals such as microbial products, complement, damaged cells and white blood cell fragments. Chemotaxis is followed by adhesion, where the phagocyte sticks to the microorganism. Adhesion is enhanced by opsonization, where proteins like opsonins are coated on the surface of the bacterium. This is followed by ingestion, in which the phagocyte extends projections, forming pseudopods that engulf the foreign organism. Finally, the bacterium is digested by the enzymes in the lysosome, involving reactive oxygen species and proteases.In addition, anti-microbial proteins may be activated if a pathogen passes through the barrier offered by skin. There are several classes of antimicrobial proteins, such as acute phase proteins (C-reactive protein, for example, enhances phagocytosis and activates complement when it binds itself to the C-protein of S. pneumoniae ), lysozyme, and the complement system.|
The innate immune system, when activated, has a wide array of effector cells and mechanisms. There are several different types of phagocytic cells, which ingest and destroy invading pathogens. The most common phagocytes are neutrophils, macrophages, and dendritic cells. Another cell type, natural killer cells are especially adept at destroying cells infected with viruses. Another component of the innate immune system is known as the complement system. Complement proteins are normally innactive components of the blood. However, when activated by the recognition of a pathogen or antibody, the various proteins are activated to recruit inflammatory cells, coat pathogens to make them more easily phagocytosed, and to make destructive pores in the surfaces of pathogens
Adaptive immunity is triggered when an infection eludes innate defenses and generates a threshold of antigen. Acquired immunity is effective only after several days, the time required for antigen-specific T and B cells to proliferate and differentiate into effector cells. Also, adaptive immunity ensures that mammals surviving an initial infection by a pathogen are generally immune to further illness from by that same pathogen. The adaptive immune system is based on T and B cells (aka leukocytes, a kind of white blood cell) that are produced by bone marrow stem cells and mature in the thymus and/or lymph nodes. The fundamental steps of acquired immunity are:
|Adherence||Antigens in tissues are trapped in draining lymph nodes, while antigens in the blood are taken to the spleen where the immune response is initiated in white pulp. Antigens in tissues spaces are uptaken by Langerhans cells, which enter lymphatics, move to lymph nodes and become antigen-presenting dendritic cells expressing B7 (a co-stimulatory molecule in addition to the antigen that is needed for T cell activation). B7 dendritic cells activate T cells.|
|T Activation||Activation of T cells occurs only in lymph nodes or white pulp -- T cells cannot be activated in peripheral tissue. Naïve T cells continually recirculate through the lymphoid organs. However, T cells tightly adhere to the APC and stop migrating if the T cell is specific to the APC's presented antigen and the T cell LFA-1 (an integrin composed of CD11a and CD18) binds APC cell-surface ICAM-1.|
|T Differentiation||A given pathogen can interact with dendritic cells (DCs), macrophages (Mφs), natural killer cells (NKs) and 1.1+CD4+ natural killer T cells (NKTs, a special kind of T cell). Each of these cell types release different cytokines, encouraging the naïve CD4 T cell to differentiate into either TH1 or TH2 cells. Differentiation into TH1 or TH2 has a critical impact on the immune response and is influenced by whichever cytokines are present. CD4 T cells develop into TH2 cells if activated in presence of IL-4, especially if IL-6 is also present. IL-4 and IL-10 inhibit differentiation into TH1. 1.1+CD4+ NKs secrete IL-4. CD4 T cells develop into TH1 cells if activated in presence of IL-12 and IFN-γ. IFN-γ inhibits differentiation of TH2 cells. IL-12 and IFN-γ are produced by mφs and NKs.|
|B Activation||B cell activation takes place in secondary lymphoid organs, such as lymph nodes. B cells specific for peptide antigens cannot be activated until they encounter an activated TH cell. Thus, B cells recirculate through lymph nodes until they encounter an activated TH1 or TH2 cell specific for the same peptide antigen they are. This activates the B cell to proliferate and differentiate. These differentiated B cells then either patrol the body for antigen, or secrete large amounts of antibody to tag pathogens for destruction.|
In many species, including mammals, the adaptive immune system can be divided into two major sections
|Humoral Immunity||Humoral immunity provides the main protective response against extracellular bacteria, by means of antibodies (aka immunoglobulin) whic are produced by B cells. Humoral immunity has aspects of both innate immunity (the thymus-independent response, where antibodies bind typical bacterial polysaccharides) and adaptive immunity (the thymus-dependent response, where antibodies bind peptide antigens.|
|Cell-Mediated Immunity||Cell-mediated immunity clears intracellular bacteria, fungi and virally infected cells via two two major kinds of thymocytes:|
In addition to determining self from non-self, the immune response has B and T cells which identify different forms of non-self. Distinguishing various forms of non-self is crucial. For example, effectively responding to a bacterial infection would have no effect on an intracellular pathogen. B and T cells rely upon subtle differences in the biochemical structures of foreign proteins, carbohydrates, lipids and other building blocks. Known as antigens, these non-self structures are the target of the immune response and cause it to produce antigen-specific antibodies in response.
The immune response can only detect bio-organic antigens, essentially limiting it only to chemicals encoded or controlled by genes. Thus, all antigens are based on carbon and the atoms which bond to carbon (hydrogen, oxygen, nitrogen, phosphorous and sulfur -- aka CHONPS). The immune response ignores any chemical not based on the six atoms listed. This means that sand, mercury, minerals and other contaminants are not subject to the immune response.
B and T cells bear receptors to distinguish self from non-self. B cells present immunoglobulin (antibody molecule) and T cells present T cell receptor (TCR). Much like enzyme binds substrate, the function of both molecules is to bind antigen. Binding of antigen by both B and T cells leads to removal of antigen from the system. The configuration of CHONPS is the antigenic determinant.
At this point, please study Clonal Expansion Theory to understand how the body specifically detects countless antigens; next, memorize important cells of the immune system to grasp the team of cells that make up the immune system.
Macrophages process pathogens and present on their cell surface antigens from the pathogen. After antigen presentation, antigen-specific cells under clonal expansion. Antigen-specific cells with high antigen affinity (due to their particular antibody configuration) respond efficiently and preferentially expand over time. This explains why subsequent responses to an antigen are anamnestic (stronger and faster) after initial exposure.
Immunity requires a primary stimulus, meaning nobody is immune to an antigen until they have been exposed to that antigen. However, some people may be resistant to an antigen for genetic reasons or may have strong innate protection. Innate responses and acquired (anamnestic) responses evolved together to confer resistance and protection against microbial invasion and malignant cells. Activation of innate immunity cells (such as via TLRs) promotes antigen-presenting cells to not only present antigens but also activate B and T cells.
Innate vs adaptive immunity
Innate and adaptive immunity are quite intertwined.
For example, antigen presentation by dendritic cells (part of the innate immune system) activates thymocytes to proliferate and differentiate (part of the adaptive immune system).
Extracellular infectionExtracellular bacteria induce inflammation by producing toxins. Endotoxins are bacterial cell wall components such as LPS; exotoxins are actively secreted and interfere with cell function, induce cytokine production and are cytotoxic. Extracellular bacteria can directly activate complement, with C1q directly binding the bacteria (classical pathway), mannose-binding protein binding the cell wall (lectin pathway) and/or C3b binding the cell surface (alternative pathway). Cleavage products of complement are opsonin, meaning they enhance phagocytosis. The F(c) region of IgG binds to F(c) receptors, playing a critical role in clearing extracellular bacteria (also, receptor for complement byproducts are important for clearance).
Intracellular bacteria are eliminated by cell-mediated immunity. The innate response consists mainly of phagocytes and NK cells; NK cells are activated either directly or by IL-12 produced by macrophages. Macrophages secrete IL-12 upon phagocytosis of bacteria, and are activated to become phagocytic by IFN-γ secreted by T cells. Also, CTLs lyse infected cells. If IL-12 and IFN-γ are present following initial pathogen exposure, the response is dominated by inflammatory thymocytes. IFN-γ and IL-12 are essential for responding to an infection by intracellular bacteria, with infected IFN-γ knockouts dying after 30 days and infected IL-12 knockouts dying after 60 days.
There are many animal parasites, ranging from protozoa (unicellular eukaryote) to helminths (large worms). The principal innate response to parasites is phagocytosis, but many parasites are resistant to phagocytosis and can even replicate within macrophages. Phagocytes secrete microbicides to kill organisms too large for phagocytosis, but many helminths have thick teguments that resist neutrophil and macrophage attacks. Also, some helminths activate complement -- but many of them are also resistant to lysis via complement.
Helminthic infections are eliminated by secretion of IL-4 and IL-5 by activated TH2 cells. IL-4 and IL-5 then stimulates production of sIgE that binds the worm. This IgE binds F(c)ε receptors on eosinophils, activating the eosinophils to secrete granule enzymes that destroy the parasite.
Some pathogenic protozoa (such as Leishmania spp.) survive within macrophages by deactivating the macrophage. Adaptive immunity is then necessary, with TH1 cells secreting large amounts of IFN-γ to re-activate the infected macrophages. Protozoa such as malaria that replicate within and lyse host cells stimulate specific antibody and CTL responses. Another parasite, trypanosomes, change the expression of their surface antigen to evade immune response.
The cells of the immune system function to combat viruses in two ways:
B cells secrete antibodies which neutralize the virus (humoral immunity) and
T cells recognize and kill infected cells (cell-mediated immunity)
Viruses replicate within cells and are either cytopathic (lyse infected cells) or noncytopathic (do not lyse infected cells). Innate immunity to viruses is controlled by: interferons, produced in response to binding of dsRNAs to TLRs; and natural killer cells, which kill cells expressing stress-induced proteins and those with decreased Class I expression. Adaptive immunity to viruses is controlled by: secreted antibodies, which block extracellular virions from binding and entering cells, and which tag infected cells presenting viral particles on their cell surface; and CTLs, which eliminate infection by killing infected cells.
Antibodies are effective during the extracellular stage, preventing virions from spreading and protecting against reinfection. sIgA is a very important part of mucosal secretions, blocking viral attachment to mucosal epithelial cells. Also, antibodies may directly activate complement-mediated lysis of virion particles with lipid envelopes.
However, once the virus enters a cell it is inaccessible to antibodies and infected cells must be eliminated by CTLS. CD8 T cells recognize viral antigens presented in a Class I MHC context on the surface of an infected cell. CTL activation requires co-stimulation -- if the virally infected cell is not an APC, then it must be phagocytosed by a professional APC. The CD8 T cell then recognizes endogenously synthesized (synthesized within the cell) viral proteins presented in a Class I MHC context on the cell surface. Cytokines produced by CD4 T cells (TH cells) drive CD8 differentiation into effector CTLs that use antigen-specificity to locate and kill infected nucleated cells.
DCs present peptides on both Class I and II MHC. T cell proliferation, indicated by H3 incorporation, indicates presentation of an immunogenic peptide on Class II while lysis indicates presentation on Class I. To mount an effective immune response against a viral infection a strong CD8 T cell response is required to kill infected cells. This requires help from CD4 T cells. Therefore, an effective vaccine requires the priming of both CD4 and CD8 T cells. Peptide 3 is presented on Class I and primes CD8 T cells against the virus while Peptide 2 primes CD4 T cells. Lysis is augmented using these peptides together because of T cell help.
|Kappa (κ) and lambda (λ) are the two light chain isotypes. Antibody light chains have a constant region (IgCL) at one end and a variable region (IgVL) at the other end. Light chain variable regions are either kappa (κ) isotype or lambda (λ) isotype. The two light chain isotypes have no known functional differences. In mammals, there is one kind of κ isotype and four kinds of λ isotype (λ1, λ2, λ3 and λ4). While an individual has both κ and λ light chains, an individual B cell only produces κ or λ. Thus, only one type of light chain is present in a typical antibody -- the two light chains of an individual antibody are identical.|
|µ||µ refers to the IgM heavy chain constant region. IgM is the predominant antibody, and the membrane receptor of naïve B lymphocytes (along with IgD). However, allelic exclusion means that only one µ allele is expressed in a single lymphocyte. For example, a heterozygote with a µa allele and a µb allele will have both IgMs present, but with individual cells only expressing one or the other. Disruption of µ membrane exon reduces immunoglobulin levels by over 95%. IgM is a potent stimulator of complement.|
|Adoptive Transfer||Type of immunization involving the transfer of “sensitized” cells, serum or other components to a recipient.|
Haptens must be bound to carriers to induce a humoral response. The same hapten-carrier conjugate must be used to elicit a secondary response; to generate a secondary response to a hapten bound to a different carrier, the patient must first be immunized against the new carrier. T cells bind carriers; B cells bind haptens. The response of hapten-primed B cells to a hapten-carrier conjugate requires carrier-primed TH cells. Remember that CTL activity only occurs with TH help.
|LCMV||LCMV is a non-cytopathic virus. Mice deficient of T cells become chronic LCMV carriers, while normal mice develop meningitis to due to CTL killing of meningeal cells. It is frequently used for experiments.|
|'C' Anything||If you see a chemical that starts with the letter 'C' (but not 'CD') then it is likely involved in complement. C3a, C4a and C5a are small-peptide byproducts of complement and are anaphylatoxins, binding mast-cells and basophils to induce degranulation and cause vascular permeability and smooth muscle contraction. Also, anaphylatoxins amplify the inflammatory response by inducing synthesis of pro-inflammatory cytokines. C5a is the most potent anaphylatoxin, and also is a chemoattractant and activator of white blood cells (macrophages, etc). C5a can attract white blood cells to extravasate from local capillaries and migrate into the tissue space where complement has been activated.|
|Phagocytes||Phagocytes have receptors which directly recognize bacteria and lead to phagocytosis, activation, microbicidal activity and cytokine secretion.|
|Macrophage||Tissue macrophages: trap, engulf and destroy pathogens; produce cytokines (including IL-12); induce co-stimulatory molecules; and present antigens for the adaptive immune response. Macrophages present antigens on their cell surface, they are known as antigen presenting cells (APCs). These antigens are then recognized by effector cells (B cells and T cells). Macrophages also bear CD14 (and LPS receptor), CD11b/CD18 complex (binds C3b and C4b, complement byproducts), scavenger receptor (binds sialic acid), TLR and F(c)R. F(c)R binds antigen-antibody complexes, absorbs them, degrades them in the lysosome and then presents the fragments on the cell surface.|
|Adaptive Immunity||Adaptive immunity is triggered when an infection eludes innate defenses and generates a threshold of antigen. Acquired immunity is effective only after several days, the time required for antigen-specific T and B cells to proliferate and differentiate into effector cells. See more at the acquired immunity overview.|
|MHC Restriction||T cells only respond to self MHC molecules. MHC restriction occurs via negative selection, which is controlled by thymic dendritic cells (aka thymic stromal cells). Thymic dendritic cells are derived from bone marrow -- thus, an irradiated mouse with transplanted bone marrow will tolerate the same MHC haplotypes as the donor. If the recipient mouse is MHCaa and the donor is MHCab, then the recipient mouse will then have T cells which react to MHCa and MHCb. The MHCa-reactive T cells which function normally, while the others will never be activated. However, if the recipient mouse is MHCaa and the donor is MHCbb, then then there will be no MHCa-reactive T cells in the periphery. This means there will be no T cells able to react with self MHC molecules, and the recipient will almost entirely lack an immune system.|
|Protective Immunity||Immunity from reinfection relies upon antibodies and armed effector T cells. Specific IgA on epithelial surfaces can neutralize a virus before it ever even enters the body. Memory B cells are responsible for antibody secretion in response to reinfection -- the secondary humoral response. Compared to a response to initial infection, the 2° humoral response is characterized by a quick response of larger magnitude, with secretion of higher-affinity antibodies of different isotypes (more IgG, instead of IgM), and higher Class II MHC levels. These changes facilitate antigen uptake and presentation, allowing memory B cells interact with armed TH cells at lower antigen doses. Memory T cells are express activated cell markers (like CD44) but the CD45 isotype is different -- CD45RA on naïve T cells and CD45RO on memory cells.|
|Tolerance||There are three mechanisms to ensure tolerance, which is selective negative immunity against self: clonal deletion, loss of certain antigen-specific cells in primary lymphoid tissues; clonal anergy, slowly-reversible induced unresponsiveness of cell population; clonal suppression, which is undone if the suppressor is removed. Clonal deletion occurs in the thymus for T cells -- positive selection (kill if bind MHC too strong) on host thymic epithelium and negative selection (kill if self-reactive) on donor-derived dendritic cells. Reactivity to non-thymic self-antigens avoided via clonal anergy, which occurs when the thymocyte binds antigen (signal 1) but is no co-stimulated (signal 2).|
|F(ab)||The fragment antigen binding (Fab fragment) is a region on an antibody which binds to antigens. The Fab fragment is monovalent and hence would not be able to crosslink the FcεRI receptors. Crosslinking is a prerequisite for degranulation. Compare to F(c).|
|MHC||Class I = CD8 CTLs; Class II = CD4 THs|
|Lysosome||Lysosomes degrade ingested particles, sometimes presenting them via Class II MHC expression. Acidifying the lysosome renders it non-functional.|
|Proteaosome||Proteaosomes degrade intracellular proteins -- the degraded peptides can be used for Class I MHC expression.|
Organs & Locations
|Bone Marrow||Site of B cell and macrophage maturation.|
|Lymph Node||B cell activation by antigens drained from tissue spaces.|
|Spleen||Blood-borne antigens are presented to B cells. B cell activation takes place in the spleen.|