Chapter 6 - Diseases of the Immune System Flashcards
Two broad categories of immunity
Innate immunity (a.k.a. natural, native immunity): mechanisms ready to react to infections before they occur. These have evolved to recognize and combat microbes. First line of defense
Adaptive immunity (a.k.a. acquired, specific immunity): Mechanisms that are stimulated by microbes and are capable of recognizing microbial and nonmicrobial substances. Develops later than, and is stronger than innate immunity.
The principal mechanisms of innate immunity and adaptive immunity. NK cells, Natural killer cells.
Innate immunity functions in three stages
- Recognition of microbes
- Activation of various mechanisms
- Elimination of unwated substances
What are the major components of innate immunity?
- Epithelial barriers (i.e. skin, GI, respiratory tract) - provide mechanical barriers to microbial entry from external environment. Epithelial cells also produce antimicrobial molecules (i.e. defensins)
- Phagocytic cells (monocytes, macrophages, neutrophils) - sense the presence of, and ingest harmful microbes
- Dendritic cells (interstitial, plasmacytoid, langerhans)- Specialized cells in epithelia, lymphoid organs, most tissues, that capture protein antigens and display them for T-lymphs to recognize. They also secrete cytokines, mediating inflammation. Key in innate immunity, not part of adaptive immunity.
- Natural killer cells - Provide early protection against viruses and intracellular bacteria
- Several other cell types (mast cells, others) can sense and react to microbes
- Innate lymphoid cells - Recently discovered cells that lack TCRs, but produce cytokines similar to T cells
- Soluble proteins (complement proteins, mannose-binding lectin, C-reactive protein)- activated by microbes using alternative and lectin pathways in innate responses; activated by antibodies in classical pathway in adaptive responses. MBL and CRP coat microbes, promoting phagocytosis of them. Lung surfactant is also part of innate immunity against inhaled microbes
Cells that participate in innate immunity are capable of recognizing certain microbial components that are shared among related microbes and are often essential for infectivity (and thus cannot be mutated to allow the microbes to evade the defense mechanisms).
What are these microbial structures called?
What are the receptors that recognize these molecules called?
Pathogen-associated molecular patterns (PAMPs)
Leukocytes also recognize molecules released by injured/necrotic cells Damage-assocaited molecular patterns (DAMPs)
Receptors are called pattern recognition receptors (PRRs)
Pattern recognition receptors are located in all the cellular compartments where microbes may be present: plasma membrane receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm.
What are some categories of PRRs?
- Toll-like receptors (TLRs)
- NOD-like receptors (NLRs) and the inflammasome
- C-type lectin receptors (CLRs)
- RIG-like receptors (RLRs)
- Mannos receptors
Toll-like receptors
Ten different TLRs in mammalian cells, each recognizing a different set of microbial molecules.
They may be present in plasma membranes or endosomal vesicles.
They all signal via a common pathway that culminates in in the activation of 2 sets of transcription factors:
(1) NF-kB - stimulates synthesis and secretion of cytokines and expression of adhesion molecules
(2) interferon regulatory factors (IRFs) - stimulates production of antiviral cytokines (type I interferons)
NOD-like receptors and the Inflammasome
NLRs are cytosolic receptors. that recognize a wide variety of substances (i.e. uric acid, ATP, ion disturbances, some microbial products)
Inflammasome: cytosolic multiprotein complex which activates caspase-1 that cleaves and activates IL-1
The inflammasome. The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin 1. The inflammasome consists of a sensor protein (a leucine-rich protein called NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to an active form.
C-type lectin receptors (CLRs)
Expressed on plasma membranes of macrophages and dendritic cells, and detect fungal glycans, eliciting an inflammatory response to fungi
RIG-like receptors (RLRs)
Cytosolic receptors in most cell types; detect nucleic acids of viruses that replicate in teh cytoplasm of infected cells.
These stimulate production of antiviral cytokines.
G protein-coupled receptors on leukocytes recognize N-formylmethionyl residues on bacterial organisms, stimulating chemotactic responses in these cells.
Mannose receptors
Recognize microbial surgars (they have terminal mannose residues, unlike mammalian glycoproteins), and induce phagocytosis of microbes)
Cellular receptors for microbes and products of cell injury. Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. The four major classes of innate immune receptors are TLRs, NOD-like receptors in the cytosol (NLRs), C-type lectin receptors (CLRs), and RIG-like receptors for viral nucleic acids (RLRs).
The innate immune systeme provides host defense by 2 main reactions:
- Inflammation: Cytokines complement fragments, other mediators, are produced during innate immune reactions and trigger vascular and cellular components of inflammation.
- Antiviral defense: Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit their replication - antiviral state
A few major differences between innate and adaptive immunity
- Innate immunity does not have memory or fine antigen specificity, like adaptive immunity has.
- Innate immunity uses about 100 receptros to recognize 1,000 molecular patterns, while adaptive immunity uses two receptor types (antibodies and TCRs), each with millions of variations
What are the two types of adaptive immunity?
There are two types of adaptive immunity: humoral immunity, which protects against extracellular microbes and their toxins, and cell-mediated immunity, which is responsible for defense against intracellular microbes.
Are lymphocytes and other cells involved in immune responses fixed in particular tissues?
No
They constantly circulate among lymphoid and other tissues via blood and lymphatic circulation
This provides immune surveillance
What are naive, effector, and memory lymphocytes?
- Naive lymphocytes - mature lymphocytes that have not yet encountered antigen for which they are specific
- Effector cells - Lymphocytes that have recognized antigen, become activated, and differentiated in order to eliminate microbes
- Memory cells - Lymphocytes that have recognized antigen, become activated, and differentiated in order to live in a state of heightened awareness and can react strongly and rapidly to combat the microbe if it returns
The principal classes of lymphocytes and their functions. B and T lymphocytes are cells of adaptive immunity and natural killer (NK) cells are cells of innate immunity. Several more classes of lymphocytes have been identified, including NK-T cells and so-called innate lymphoid cells (ILCs); the functions of these cells are not established.
What is the fundamental concept of clonal selection?
Lymphocytes specific for a large number of antigens exist before exposure to antigen, and when an antigen enters, it selectively activates the antigen-specific cells.
Clones - Lymphocytes of the same specificity that express identical antigen receptors.
With 1012 lymphocytes that are capable of recognizing 107-109 different antigens, there are very low numbers of cells specific for any one antigen
What generates antigen receptor diversity?
Antigen receptor diversity is generated by somatic recombination of genes that encode the receptor proteins.
Recombination activating genes (RAG-1, RAG-2) produce enzymes in developing lymphocytes that mediate gene recombination.
All cells in the body contain the germline antigen receptor genes, but only T and B cells contain recombined gnees (TCR, Ig)
Each T or B cell and its clonal progeny have a unique DNA rearrangement (and a unique antigen receptor). What is the clinical significance of this?
It is possible to distinguish polyclonal (nonneoplastic) from monoclonal (neoplastic) lymphoid proliferations. Analysis of antigen receptor gene rearrangement is a valuable assay for detecting tumors derived from lymphocytes.
What are the three major populations of T lymphocytes?
1. Helper T lymphocytes stimulate B lymphocytes to make antibodies and activate other leukocytes to destroy microbes.
2. Cytotoxic T lymphocytes kill infected cells
3. Regulatory T lymphocytes limit immune responses and prevent reactions against self-antigens.
Where do T cells mature and where are mature ones located?
T cells develop in the thymus from precursors that arise from hematopoietic stem cells.
Mature T cells are in the blood, where they constitute 60-70% of lymphocytes, and are in T-cell zones of peripheral lymphoid organs.
T cell receptor (TCR) structure and function
TCR consists of a heterodimer made up of an alpha and a beta polypeptide chain, each with a variable antigen binding and a constant region.
Each TCR is linked to an invariant CD3/zeta protein complex (6 polypeptide chains), w hich is involved in signal transduction
TCR + this complex = TCR complex
The ab-TCR recognizes peptide antigens that are presented by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells.
A small population of mature T cells have a gamma-delta (yd) TCR which recognizes peptides, lipids, and small molecules WITHOUT the need for MHC proteins. These aggregate at epithelial surfaces (GI, resp, urogen, skin), which may indicate they are sentinels, but their functions are unknown
The T-cell receptor (TCR) complex and other molecules involved in T-cell activation. The TCR heterodimer, consisting of an α and a β chain, recognizes antigen (in the form of peptide-MHC complexes expressed on antigen-presenting cells, or APCs), and the linked CD3 complex and ζ chains initiate activating signals. CD4 and CD28 are also involved in T-cell activation. (Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.) The sizes of the molecules are not drawn to scale. MHC, Major histocompatibility complex.
In addition to CD3 and zeta proteins, T cells express several other proteins that assist the TCR complex in functional responses. What are some of these?
- CD4 - coreceptor for T helper cells that binds to MHC II molecules (expressed on professional APCs) (~ 60% of mature T cells)
- CD8 - coreceptor for cytotoxic t cells that binds to MHC I molecules (~30% of mature T cells)
- CD28 - Recognize signals from antigen-presenting cells
- Integrins - cell-cell and cell-matrix adhesion
What is the only cell in the body capable of producing antibodys and ar mediators of humoral immunity?
B-cells!
They develop from precursors in the marrow; mature B-cells comprise 10-20% of circulating peripheral lymphocyte population and are present in peripheral lymphoid tissues (LNs, spleen, MALT)
How do B-cells recognize antigen?
Through the B-cell antigen receptor complex
Membrane-bound antibodies (IgM and IgD) are on all mature, naive B cells and are the antigen-binding component of the B-cell receptor complex
B-cell antigen receptor complex also contains a heterodimer of two invariant proteins (Ig-alpha (CD79a), and Ig-beta (CD79b)), which are essential for signal transduction.
B-cells also express:
(1) Type 2 complement receptor (CR2, or CD21) which recognizes complement products generated during innate immunity (CR2 is also used by Epstein-Barr virus as a receptor to enter/infect B cells)
(2) CD40 - receives signals from helper T cells
Structure of antibodies and the B-cell antigen receptor. A, The B-cell antigen receptor complex is composed of membrane immunoglobulin M (IgM; or IgD, not shown), which recognizes antigens, and the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that also promotes B-cell activation. B, Crystal structure of a secreted IgG molecule, showing the arrangement of the variable (V) and constant (C) regions of the heavy (H) and light (L) chains.
Dendritic cells in adaptive immunity
Dendritic cells are the most important antigen-presenting cells for initiating T-cell responses against protein antigens.
These have fine cytoplasmic processes (dendrites)
Langerhans dendritic cells are within the epidermis (skin, repro, resp, GI tracts)
Interstitial dendritic cells are in all organs except brain (are in choroid plexus and meninges) and are subepithelial
Dendritic cells express many receptors for capturing and responding to antigens (i.e. TLRs, lectins)
In response to microbes, they are recruited to T-cell zones of lymphoid organs where they present antigen via MHCII
Another type of dendritic cell (follicular/plasmacytoid dendritic cell) lives in germinal centers of lymphoid follicles in spleen and LNs, and have receptors for IgG Fc regions and C3b, and can trap antigen that is bound to antibodies/complement. They present antigen to B cells and select the B cells with the highest affinity for the antigen
Macrophages - adaptive immunity
- Macs that have eaten microbes/protein antigens process antigens and present peptide fragments to T-cells
- Macs are key effector cells in certain forms of cell-mediated immunity. T-cells activate macrophages and enhance their phagocytic activity.
- Macs participate in the effector stage of humoral immunity by phagocytosing and destroying opsonized (IgG or C3b) microbes
Natural Killer cells - adaptive immunity
The function of NK cells is to destroy irreversibly stressed and abnormal cells, such as virus-infected cells and tumor cells.
Make up 5-10% of peripheral blood lymphocytes, and do not express TCRs or Ig. These contain azurophilic granules
CD16 (Fc receptor for IgG so they can lyse IgG-coated cells - antibody-dependent cell-mediated cytotoxicity (ADCC)), CD56 (function unknown) used to identify NK cells
Functional activity of NK cells is regulated by a balance between signals from activating and inhibitory receptors.
NK cells secrete cytokines (IFN-y) which activate macrophages to destroy ingested microbes, thus providing an early defense against intracellular infections.
IL-2, IL-15 –> stimulate NK proliferation
IL-12 –> activates killing and secretion of IFN-y
Activating and inhibitory receptors of NK cells
Activating: NKG2D family is the best characterized group of activating receptors on NK cells. Recognizes surface molecules induced by various stresses (i.e. DNA damage, infection)
Inhibitory: Receptors recognize MHCI molecules which are expressed on healthy normal cells. Inhibitory receptors prevent NK cells from killing normal cells. Viral infection/neoplastic transformation often reduces MHCI expression.
Activating and inhibitory receptors of natural killer (NK) cells. A, Healthy cells express self class I MHC molecules, which are recognized by inhibitory receptors, thus ensuring that NK cells do not attack normal cells. Note that healthy cells may express ligands for activating receptors (not shown) or may not express such ligands (as shown), but they do not activate NK cells because they engage the inhibitory receptors. B, In infected and stressed cells, class I MHC expression is reduced so that the inhibitory receptors are not engaged, and ligands for activating receptors are expressed. The result is that NK cells are activated and the infected cells are killed.
Innate lymphoid cells (ILCs)
Recently discovered group of lymphocytes that lack TCRs but produce cytokines similar to those made by T cells.
NK cells are the first defined ILC
Different subsets produce IFN-y, IL-5, IL17, IL22
Functions:
(1) Early defense against infections
(2) recognition and elimination of stressed cells
(3) shaping later adaptive immunity by providing cytokines that influence T-cell differentation
Generative (primary, central) lymphoid organs
The principal generative lymphoid organs are the thymus, where T cells develop, and the bone marrow, the site of production of all blood cells and where B lymphocytes mature.
Peripheral (secondary) lymphoid organs
The peripheral lymphoid oragns – lymph nodes, spleen, and mucosal/cutaneous lymphoid tissues – are organized to concentrate antigens, antigen-presenting cells, and lymphocytes in a way that optimizes interactions among these cells and teh development of adaptive immune responses.
Lymph nodes- nodular aggregates of lymphoid tissues along lymphatic channels throughout the body. Lymph suffuses through lymph nodes, allowing nodal APCs to sample antigens that came in through epithelia. Dendritic cells from the epithelia also carry antigens in lymph to LNs
Spleen- Abdominal organ that serves the same role in immunity to bloodborne antigen as lymph nodes do to lymph-borne antigens.
MALT/CALT- located under epithelia of skin, GI, and respiratory tracts that respond to antigens that breach epithelium. (i.e. pharyngeal tonsils, peyer’s patches of intestines). > 50% of body’s lymphs are in mucosal tissue at any time (many are memory lymphs)
Anatomy of peripheral lymphoid organs
T- and B- lymphocytes are segregated into different regions.
Lymph nodes- B cells and follicular dendritic cells are concentrated into follicles, located around the periphery (cortex) of each node. If the B cells have recently responded to an antigen, follicle may contain a central germinal center. T lymphocytes and APCs that present to T lymphs are concentrated in paracortex, adjacent to follicles.
Spleen- T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles. B lymphocytes reside in the follicles.
Morphology of a lymph node.
A, The histology of a lymph node, with an outer cortex containing follicles and an inner medulla.
B, The segregation of B cells and T cells in different regions of the lymph node, illustrated schematically.
C, The location of B cells (stained green, using the immunofluorescence technique) and T cells (stained red) in a lymph node.
Lymphocyte recirculation
Lymphocytes constantly recirculate between tissues and home to particular sites; naive lymphocytes traverse the peripheral lymphoid organs where immune responses are initiated, and effector lymphocytes migrate to sites of infection and inflammation.
Most important for T-cells
What is the function of MHC molecules?
The function of MHC molecules is to display peptide fragments of protein antigens for recognition by antigen-specific T cells.
MHCI - structure, cellular distribution, function
Structure: Heterodimers with a polymorphic a (heavy) chain linked to a NONpolymorphic b2-microglobulin. Extracellular face of a-chain has 3 domains (a1, a2 form a cleft for peptide binding)
Cellular distribution: Expressed on all nucleated cells and platelets
Function: **Class I MHC molecules display peptides that are derived from proteins, such as viral and tumor anitgens, that are located in the cytoplasm and usually produced in the cell, and class I-associated peptides are recognized by CD8+ T lymphocytes**. The nonpolymorphic a3 subunit binds CD8 in T cells, as the TCR binds MHCI
MHCII - structure, cellular distribution, function
Structure: heterodimer consisting of an a-chain and a b-chain, both of which are polymorphic. Extracellular portions of a- and b- chains have 2 domains (a1, a2, b1, b2). Peptide-binding cleft is formed by a1-b1 domains
Cellular distribution: Mainly expressed on professional antigen presenting cells (Dendritic cells, macrophages, B-lymphocytes)
Function: Class II MHC molecules present antigens that are internalized into vesicles, and are typically derived from extracellular microbes and soluble proteins.
The human leukocyte antigen (HLA) complex and the structure of HLA molecules.
A, The location of genes in the HLA complex. The relative locations, sizes, and distances between genes are not to scale. Genes that encode several proteins involved in antigen processing (the TAP transporter, components of the proteasome, and HLA-DM) are located in the class II region (not shown).
B, Schematic diagrams and crystal structures of class I and class II HLA molecules.
The induction and regulation of immune responses involve multiple interactions among lymphocytes, dendritic cells, macrophages, other inflammatory cells, and endothelial cells. Some of these interactions depend on cell-cell contact; however, many cellular interactions and functions of leukocytes are mediated by secreted proteins called _______.
Cytokines
The majority of cytokines act in an _____ or ______ fashion, rather than an _____ fashion.
Autocrine or paracrine
rather than an endocrine
Cytokines contribute to different types of immune responses:
- Innate immunity - cytokines produced rapidly after microbial or antigenic stimulation, and function to induce inflammation and inhibit viral replication. TNF, IL-1, IL-12, type I IFNs, IFN-y, chemokines are important here. Major sources for these are macrophages, dendritic cells, NK cells (endo/epi thelial cells also can produce)
- Adaptive immunity - Cytokines produced principally by CD4+ T lymphocytes activated by antigen and other signals. They function to promote lymphocytes proliferation and differentiation and to activate effector cells. Main ones here are IL-2, IL-4, IL-5, IL-17, IFN-y. Some cytokines (TGF-b, IL-10) limit the immune responses.
- Colony-stimulating factors (i.e. GM-CSF, G-CSF) stimulate hematopoiesis during cytopenic states. These are produced by marrow stromal cells, T-lymphs, macrophages, others. IL-7 important here too.
Steps of the adaptive immune response
- Antigen recognition
- Activation of specific lympocytes to proliferate and differentiate into effector/memory cells
- Elimination of the antigen
- Decline of the response
Display and recognition of antigens - overview
- Antigens are captured and concentrated in lymphoid organs where lymhocytes circulate (carried there by APCs)
- Prior to microbial recognition by lymphocytes, the microbe elicits an innate immune response through PRR signaling.
- During immunization, adjuvants are given with the antigen; adjuvant and/or antigen activates APCs to express costimulators (CD80, CD86) which are recognized by CD28 on naive T cells. These two signals (antigen and costimulatory molecules) activate antigen-specific lymphocytes.
Cell-mediated immunity. Dendritic cells (DCs) capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During this process, the DCs mature, and express high levels of MHC molecules and costimulators. Naive T cells recognize MHC-associated peptide antigens displayed on DCs. The T cells are activated to proliferate and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. CD4+ effector T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes, and activate the phagocytes to kill the microbes; other subsets of effector cells enhance leukocyte recruitment and stimulate different types of immune responses. CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Some activated T cells remain in the lymphoid organs and help B cells to produce antibodies, and some T cells differentiate into long-lived memory cells (not shown). APC, Antigen-presenting cell.
Subsets of helper T (TH) cells. In response to stimuli (mainly cytokines) present at the time of antigen recognition, naive CD4+ T cells may differentiate into populations of effector cells that produce distinct sets of cytokines and perform different functions. The dominant immune reactions elicited by each subset, and its role in host defense and immunologic diseases, are summarized. These populations may be capable of converting from one to another. Some activated T cells produce multiple cytokines and do not fall into a distinct subset. IBD, inflammatory bowel disease; MS, multiple sclerosis.
Humoral immunity. Naive B lymphocytes recognize antigens, and under the influence of TH cells and other stimuli (not shown), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy-chain classes (isotypes) perform different effector functions, shown on the right. Note that the antibodies shown are IgG; these and IgM activate complement; and the specialized functions of IgA (mucosal immunity) and IgE (mast cell and eosinophil activation) are not shown.
KEY CONCEPTS: The normal immune response
TABLE - Mechanisms of hypersensitivity reactions
Many local type I hypersensitivity reactions have 2 well-defined phases.
- Immediate reaction* - vasodilation, vascular leakage
- Late-phase reaction* - 2-24 hours later, characterized by tissue infiltration with eosinophils, neutrophils, basophils, monocytes, CD4+ lymphs
Most immediate hypersensitivity disorders are caused by excessive Th2 responses and these cells play a central role by stimulating IgE production and promoting inflammation.
Type I hypersensitivity: Sequence of events
- Activation of Th2 cells and IgE production
- Dendritic cells present antigen to naive CD4+ T cells, which differentiate (under IL-4 influence) into Th2 cells and produce numerous cytokines (IL-4, IL-5, IL-13)
- IL-4 stimulated B cells to class switch to IgE, promotes more Th2 development, and promotes eosinophil activation
- IL-5 activates eosinophils
- IL-13 enhances IgE production and simtulates mucus secretion - Sensitization and activation of mast cells
- Mast cells activated by cross-linking of high-affinity IgE Fc receptors, by anaphylatoxins (C3a, C5a)
- When a mast cell, armed with IgE previously produced in response to an antigen, is exposed to the same antigen, the cell is activated, leading to release of powerful mediators responsible for clinical features of type I hypersensitivity reactions - Mast cell degranulation and discharge of mediators
- Preformed mediators within mast cells are the first to be released; there are three categories:
(1) Vasoactive amines (histamine) - smooth mm contraction, increased vascular permeability, mucus secretion
(2) Enzymes (chymase, tryptase)- tissue damage
(3) Proteoglycans (heparin, chondroitin sulfate) - package and store amines in granules
- Lipid mediators come from conversion of membrane phospholipids to arachidonic acid
(1) Leukotrienes (C4, D4 are most potent)
(2) Prostaglandin D2
(3) Platelet-activating factor (PAF)
- Cytokines from mast cells (TNF, IL-1, chemokines, IL-4, others)
* *These are responsible for manifestations of immediate hypersensitivity reactions**
Mast cell mediators. Upon activation, mast cells release various classes of mediators that are responsible for the immediate and late-phase reactions. PAF, Platelet-activating factor.
TABLE: Examples of type I hypersensitivity disease
KEY CONCEPTS - TYPE I HYPERSENSITIVITY
Mechanisms of antibody-mediated injury.
TABLE - Examples of antibody-mediated disease (type II hypersensitivity)
Immune complex disease. The sequential phases in the induction of systemic immune complex–mediated diseases (type III hypersensitivity).
TABLE: Examples of Type III hypersensitivity disease
KEY CONCEPTS: Pathogenesis of diseases caused by antibodies and immune complexes
Granulomatous inflammation.
A, A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells.
B, The events that give rise to the formation of granulomas in type IV hypersensitivity reactions, illustrating the role of TH1 cytokines. In some granulomas (e.g., in schistosomiasis), TH2 cells contribute to the lesions. The role of TH17 cells in granuloma formation is not known.
KEY CONCEPTS: Mechanisms of T Cell-Mediated Hypersensitivity Reactions
Mechanisms of immunologic tolerance to self antigens. The principal mechanisms of central and peripheral self-tolerance in T and B cells are illustrated. APC, Antigen-presenting cell.
Pathogenesis of autoimmunity. Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers (such as infections, tissue injury, and inflammation) that promote lymphocyte entry into tissues, activation of self-reactive lymphocytes, and tissue damage.
Postulated role of infections in autoimmunity. Infections may promote activation of self-reactive lymphocytes by inducing the expression of costimulators (A), or microbial antigens may mimic self antigens and activate self-reactive lymphocytes as a cross-reaction (B).
KEY CONCEPTS: Immunologic tolerance and autoimmunity
Model for the pathogenesis of systemic lupus erythematosus. In this hypothetical model, susceptibility genes interfere with the maintenance of self-tolerance and external triggers lead to persistence of nuclear antigens. The result is an antibody response against self nuclear antigens, which is amplified by the action of nucleic acids on dendritic cells (DCs) and B cells, and the production of type 1 interferons. TLRs, Toll-like receptors.
MORPHOLOGY - SLE
Pathogenesis of amyloidosis, showing the proposed mechanisms underlying deposition of the major forms of amyloid fibrils.
