The inflammatory response is characterized by the following three events:
Soluble mediators involved in the inflammatory response:
The most important function of the human immune system occurs at the cellular level of the blood and tissues. The lymphatic and blood circulation systems are highways for specialized white blood cells to travel around the body. White blood cells include B cells, T cells, natural killer cells, and macrophages. Each has a different responsibility, but all function together with the primary objective of recognizing, attacking and destroying bacteria, viruses, cancer cells, and all substances seen as foreign. Without this coordinated effort, a person would not be able to survive more than a few days, before succumbing to overwhelming infection.
Infections set off an alarm that alerts the immune system to bring out its defensive weapons. Natural killer cells and macrophages rush to the scene to gobble up and digest infected cells. If the first line of defense fails to control the threat, antibodies, produced by the B cells, upon the order of T helper cells, are custom-designed to hone in on the invader.
Many disorders of the human immune system fall into two broad categories that are characterized by:
| Attenuated Response | There are ‘congenital’ (inborn) and ‘acquired’ forms of immunodeficiency, characterized by an attenuated response. Chronic granulomatous disease, in which phagocytes have trouble destroying pathogens, is an example of the former, while AIDS (“Acquired Immune Deficiency Syndrome”), an infectious disease caused by the HIV virus that destroys CD4+ T cells, is an example of the latter. Immunosuppressive medication intentionally induces an immunodeficiency in order to prevent rejection of transplanted organs. |
| Overzealous Response | On the other end of the scale, an overactive immune system figures in a number of other disorders, particularly autoimmune disorders such as lupus erythematosus, type I diabetes (sometimes called “juvenile onset diabetes”), multiple sclerosis, psoriasis, and rheumatoid arthritis. In these, the immune system fails to properly distinguish between self and non-self, and attacks a part of the patient’s own body. Other examples of overzealous immune responses in disease include hypersensitivities, such as allergies and asthma. |
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:
| Defense | Overview |
| 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
At this point, please study acquired immunity and its suggested reading. After, please continue to pattern-recognition receptors.
Note: This author uses the phrases ‘acquired immunity’ and ‘adaptive immunity’ interchangeably. ‘Immune response’ refers to aspects of the immune system which are antigen-specific.
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:
| Step | Overview |
| 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. |
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). In many species, including mammals, the adaptive immune system can be divided into two major sections:
| Immune System | Overview | |
| 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:
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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.
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.
| System | Includes | Overview |
| Innate Immunity | Anatomic barriers Physiologic barriers Endocytosis Phagocytosis Inflammation |
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 Antibodies |
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).
Fundamentally, the immune system relies upon two methods for protecting the host: antigen elimination and inflammation. 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.
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