Chapter 6 - Diseases of the Immune System Flashcards
1
Q
Two broad categories of immunity
A
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.
2
Q
A
The principal mechanisms of innate immunity and adaptive immunity. NK cells, Natural killer cells.
3
Q
Innate immunity functions in three stages
A
- Recognition of microbes
- Activation of various mechanisms
- Elimination of unwated substances
4
Q
What are the major components of innate immunity?
A
- 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
5
Q
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?
A
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)
6
Q
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?
A
- Toll-like receptors (TLRs)
- NOD-like receptors (NLRs) and the inflammasome
- C-type lectin receptors (CLRs)
- RIG-like receptors (RLRs)
- Mannos receptors
7
Q
Toll-like receptors
A
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)
8
Q
NOD-like receptors and the Inflammasome
A
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
9
Q
A
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.
10
Q
C-type lectin receptors (CLRs)
A
Expressed on plasma membranes of macrophages and dendritic cells, and detect fungal glycans, eliciting an inflammatory response to fungi
11
Q
RIG-like receptors (RLRs)
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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.
12
Q
Mannose receptors
A
Recognize microbial surgars (they have terminal mannose residues, unlike mammalian glycoproteins), and induce phagocytosis of microbes)
13
Q
A
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).
14
Q
The innate immune systeme provides host defense by 2 main reactions:
A
- 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
15
Q
A few major differences between innate and adaptive immunity
A
- 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
16
Q
What are the two types of adaptive immunity?
A
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.
17
Q
Are lymphocytes and other cells involved in immune responses fixed in particular tissues?
A
No
They constantly circulate among lymphoid and other tissues via blood and lymphatic circulation
This provides immune surveillance
18
Q
What are naive, effector, and memory lymphocytes?
A
- 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
19
Q
A
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.
20
Q
What is the fundamental concept of clonal selection?
A
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
21
Q
What generates antigen receptor diversity?
A
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)
22
Q
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?
A
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.
23
Q
What are the three major populations of T lymphocytes?
A
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.
24
Q
Where do T cells mature and where are mature ones located?
A
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.
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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
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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.
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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?
1. CD4 - coreceptor for T helper cells that binds to MHC II molecules (expressed on professional APCs) (~ 60% of mature T cells)
2. CD8 - coreceptor for cytotoxic t cells that binds to MHC I molecules (~30% of mature T cells)
3. CD28 - Recognize signals from antigen-presenting cells
4. Integrins - cell-cell and cell-matrix adhesion
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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)
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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
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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.
31
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
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Macrophages - adaptive immunity
1. Macs that have eaten microbes/protein antigens process antigens and present peptide fragments to T-cells
2. Macs are key effector cells in certain forms of cell-mediated immunity. T-cells activate macrophages and enhance their phagocytic activity.
3. Macs participate in the effector stage of humoral immunity by phagocytosing and destroying opsonized (IgG or C3b) microbes
33
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
34
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.
35
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.
36
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
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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.**
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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)
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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.
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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.
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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
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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.**
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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
```
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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.**
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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.
46
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*
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The majority of cytokines act in an _____ or ______ fashion, rather than an _____ fashion.
_Autocrine_ or _paracrine_
rather than an _endocrine_
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Cytokines contribute to different types of immune responses:
1. 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)
2. 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.
3. 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.
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Steps of the adaptive immune response
1. Antigen recognition
2. Activation of specific lympocytes to proliferate and differentiate into effector/memory cells
3. Elimination of the antigen
4. Decline of the response
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Display and recognition of antigens - overview
1. Antigens are captured and concentrated in lymphoid organs where lymhocytes circulate (carried there by APCs)
2. Prior to microbial recognition by lymphocytes, the microbe elicits an innate immune response through PRR signaling.
3. 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.
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Cell-mediated immunity: Activation of T lymphocytes and Elimination of intracellular microbes - Overview
1. Early response of CD4+ helper T cells - secretion of IL-2 and expression of high-affinity IL-2 receptors. IL-2 stimulates proliferation of lymphocytes to make more antigen-specific lymphs.
2. T helper cell function is mediated by CD40 ligand (CD40L) and cytokines: When CD4+ T cells recognize antigens displayed on MHC, T cells express CD40L, which binds CD40 on the macs/B cells and activates them.
3. **Some of the activated CD4+ T cells differentiate into effector cells that secrete different sets of cytokines and perform different functions.**
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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.
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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.
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Humoral immunity: Activation of B lymphocytes and elimination of extracellular microbes - Overview
1. **Upon activation, B lymphocytes proliferate and differentiate into plasma cells that secrete different classes of antibodies with distinct functions.**
2. T-dependent antibody responses are complex: B-cells ingest, degrade, and display proteins on MHC II molecules to helper T cells which are activated and express CD40L, and secrete cytokines, which work together to stimulate B cells.
3. T-independent antibody responses are more simple: Many polysaccharide and lipid antigens have epitopes that engage many antigen receptor molecules on each B cell and initiate B cell activation.
4. Polysaccharide/lipid antigens stimulate IgM production once the B cell differentiates into plasma cells. Protein antigen (via CD40L- and cytokine-mediated helper T-cell action) stimulates production of different classes (IgG, IgA, IgE)
5. *Isotype switching* is induced by cytokines (e.g. IFN-y, IL-4). *Affinity maturation-* Helper T cells stimulate antibody production with high affinities for the antigen. These are related to T-dependent processes, and occur mainly in germinal centers. The helper T cells that stimulate these processes reside in germinal centers, and are called *follecular helper T cells* (TFH).
5.
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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.
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Decline of immune responses and immunologic memory
Most effector lymphocytes induced by antigens die by apoptosis after the microbe is eliminated.
Initial activation of lymphs also generates long-lived memory cells, which survive for years and are antigen-specific.
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KEY CONCEPTS: The normal immune response
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**Injurious immune reactions, called *hypersensitivity*, are the basis of the pathology associated with immunologic diseases.** What are several important general features of hypersensitivity disorders?
1. **Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobial) or endogenous self antigens.**
2. **Hypersensitivity usually results from an imbalance between effector mechanisms of immune responses and control mechanisms that serve to normally limit such responses.**
3. **The development of hypersensitivity diseases (allergic and autoimmune) is often associated with the inheritance of particular susceptibility genes.** (i.e. HLA and non-HLA genes)
4. **The mechanisms of tissue injury in hypersensitivity reactions are the same as teh effector mechanisms of defense against infectious pathogens.**
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Main types of hypersensitivity reactions
1. Immediate hypersensitivity (type I) - injury caused by Th2 cells, IgE antibodies, mast cells, other leukocytes
2. Antibody - mediated disorders (type II) - Secreted IgG and IgM injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation
3. Immune complex-mediated disorders (type III) - IgG, IgM bind antigens in circulation and the antigen-antibody complexes deposit in tissues and induce inflammation. Tissue damage caused by lysosomal enzyme release and free radical generation
4. Cell-mediated immune disorders (type IV) - sensitized T lymphocytes (Th1, Th17, CTLs) are the cause of tissue injury.
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TABLE - Mechanisms of hypersensitivity reactions
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Type I hypersensitivity definition
**Immediate hypersensitivity is a rapid immunologic reaction occurring in a previously sensitized individual that is triggered by the binding of an antigen to IgE antibody on the surface of mast cells (i.e. allergy)**
This can occur as a local (rash, blisters, nasal/conjunctival discharge, asthma, gastroenteritis), or systemic reaction
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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.**
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Type I hypersensitivity: Sequence of events
1. 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
2. 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**
3. 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**
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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.
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Type I Hypersensitivity: Late-phase reaction
**In the late-phase reaction, leukocytes (eosinophils mainly) are recruited that amplify and sustain the inflammatory response without additional exposure to the triggering antigen.**
Eotaxin (from mast cells and Th2 cells) and other chemokines pull in eosinophils. IL-5 (from Th2) is potent eosinophil activator
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Type I hypersensitivity: Development of allergies
**Susceptibility to immediate hypersensitivity reactions is genetically determined.** *Atopy* - increased susceptibility to these reactions
**Environmental factors are also important in development in allergies**
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Type I hypersensitivity: Systemic anaphylaxis and local immediate reactions
Systemic anaphylaxis - characterized by vascular shock, widespread edema, difficulty breathing
Local immediate reactions - include urticaria, allergic rhinitis, bronchial asthma
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TABLE: Examples of type I hypersensitivity disease
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KEY CONCEPTS - TYPE I HYPERSENSITIVITY
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Type II hypersensitivty (Antibody-mediated)
**Antibodies that react with antigens present on cell surfaces or in the ECM cause disease by destroying these cells, triggering inflammation, or interfering with normal functions**.
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Type II hypersensitivity: antibody-dependent mechanisms causing tissue injury
1. Opsonization and phagocytosis
- Cells opsonized by IgG are recognized by Fc receptors on phagocytes
- IgM or IgG Abs deposited on cell surfaces may activate complement system, producing C3b, C4b which are recognized by phagocytes --\> membrane attack complex --\> destruction of cells
- Antibody-dependent cellular cytotoxicity (ADCC) - cells coated with IgG are killed by NK cells/macropahges and cell lysis w/o phagocytosis occurs
- Antibody-mediated cell destruction occurs in:
(1) Transfusion reactions
(2) hemolytic disease of newborns
(3) autoimmune hemolytic anemia/thrombocytopenia/neutropenia
(4) Certain drug reactions (haptens attach to red cell membranes)
2. Inflammation
- antibodies deposited in fixed tissues --\> complement (C5a) generation and granulocyte chemotaxis. C3a, C5a (anaphylatoxins) also increase vascular permeability
- Antibody-mediated inflammation is the mechanism responsible for glomerulonephritis
3. Cellular dysfunction
- Antibodies directed against cell surface receptors dysregulate cell function without cell injury/inflammation
- Myasthenia gravis - antibodies for Ach receptors
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Mechanisms of antibody-mediated injury.
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TABLE - Examples of antibody-mediated disease (type II hypersensitivity)
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Type III Hypersensitivity (Immune-complex mediated)
**Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition.**
Exogenous or endogenous antigen combines with antibody (usually in circulation, sometimes in situ) and deposit in vessel walls
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Type III Hypersensitivity: Systemic immune complex disease
*Acute serum sickness -* prototype of systemic immune complex disease, used to be a frequent sequela to administration of foreign serum
Three phases of pathogenesis of systemic immune complex disease:
* *1. Formation of immune complexes**
* *2. Deposition of immune complexes** (organs where blood is filtered at high pressure - joints, urine - are where they tend to deposit)
* *3. Inflammation and tissue injury** - about 10 days post antigen administration, clinical signs emerge (urticaria, joint pains, fever, LN enlargement, proteinuria)
Complement-fixing antibodies (IgG, IgM) and leukocyte Fc binding antibodies induce these lesions
Acute vasculitis and **fibrinoid necrosis** occur
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Type III Hypersensitivity: Local immune complex disease (Arthus reaction)
Arthus reaction - localized tissue necrosis from acute immune complex vasculitis, usually in the skin.
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Immune complex disease. The sequential phases in the induction of systemic immune complex–mediated diseases (type III hypersensitivity).
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TABLE: Examples of Type III hypersensitivity disease
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KEY CONCEPTS: Pathogenesis of diseases caused by antibodies and immune complexes
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Type IV Hypersensitivity (T Cell-Mediated)
**The cell-mediated type of hypersensitivity is caused by inflammation resulting from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells**
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Type IV Hypersensitivity: CD4+ T cell-mediated inflammation
**In CD4+ T cell-mediated hypersensitivity reactions, cytokines produced by T cells induce inflammation that may be chronic and destructive.**
The prototype is *delayed-type hypersensitivity (DTH) -* antigen given to previously immunized individual causes a cutaneous reaction 1-2 days later (Th1 and Th17 cells contribute)
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Type IV hypersensitivity: Activation of CD4+ T cells
CD4+ T cells recognize peptides displayed by dendritic cells and secrete IL-2, an autocrine growth factor that stimulates proliferaiton of antigen-responsive T-cells
Differentiation of antigen-stimulated T cells to Th1: Driven by IL-12 from APCs; Th1 cells then produce IFN-y which promotes further Th1 development
Differentiation of antigen-stimulated T cells to Th17: Driven by IL-1, IL-6, IL-23 from APCs
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Type IV hypersensitivity: Responses of differentiated effector T cells
Th1 cells, upon repeat exposure to antigen, secrete IFN-y, which is responsible for many manifestations of delayed-type hypersensitivity. IFN-y-activated macs (classic activation) augment phagocytosis and microbe killing and antigen presentation, and secrete pro-inflammatory cytokines (TNF, IL-1, chemokines), and they produce more IL-12, amplifying Th1 response
Activated TH17 cells secrete IL-17, IL-22, chemokines, recruiting neutrophils and monocytes and promoting inflammation. They also produce IL-21, amplifying Th17 response
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Type IV hypersensitivity: Clinical examples of CD4+ T cell-mediated inflammatory reactions
Tuberculin reaction - reddening, induration of site starts at 8-12 hours, peaks at 1-3 days. Histology shows many CD4+ T cells, macrophages, producing perivascular cuffing
With persistent antigens, macrophages dominate the infiltrate for 2-3 weeks, becoming epithelioid, creating granulomas.
*Contact dermatitis* - Poison ivy/oak, causes vesicular dermatitis. The chemical (urushiol) binds and modifies self proteins, which are recognized by T cells. This is responsible for most drug reactions
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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.
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Type IV hypersensitivity: CD8+ T cell-mediated cytotoxicity
Antigen-expressing target cells killed by CTLs
This may be important in type 1 diabetes, graft rejections, and viral infections.
Principal mechanism involves perforins and granzymes, pre-formed medaitors in CTL granules, which enter the target cell and induce apoptosis
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KEY CONCEPTS: Mechanisms of T Cell-Mediated Hypersensitivity Reactions
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Autoimmunity - definition
Immune reactions against self antigens
Autoimmune antibodies can be found in the serum of normal (especially older) animals.
* Pathologic autoimmunity* should meet three requirements:
(1) Presence of an immune reaction specific for some self antigen
(2) Evidence that such a reaction is not secondary to tissue damage, but is of primary pathogenic significance
(3) Absence of another well-defined cause of disease
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Examples of organ specific, and systemic/generalized autoimmune disease
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Organ-specific diseases:
Type 1 diabetes mellitus (endocrine pancreas)
Multiple scerlosis (CNS)
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Systemic/generalized autoimmune diseases:
Systemic lupus erythematosus (SLE) - antibodies directed against DNA, platelets, red cells, protein-phospholipids result in widespread lesions
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Immunologic tolerance definition and types
**Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen.**
*Self-tolerance* refers to the lack of responsiveness to an individual's own antigen, and it underlies our ability to live in harmony with our cells and tissues.
Central tolerance - immature self-reactive T and B lymphocytes that recognize self antigens during maturation in central lymphoid organs (thymus and bone marrow) are killed or rendered harmless
Peripheral tolerance - Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues - several mechanisms involved
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Central tolerance - concepts
In developing T cells, random somatic gene rearrangements result in diverse TCRs, producing many lymphocytes with high affinity receptors for self-antigens.
* Negative selection / deletion:* self-reactive, immature lymphocytes encounter antigens in the thymus and die by apoptosis
- Thymic APCs process and present self antigens with MHC molecules, which can be recognized by self-reactive T cells.
-**AIRE (autoimmune regulator)** is a protein that stimulates expression of some 'peripheral tissue-restricted' self antigens in thymus, and is critical for deletion of immature self-reactive T-cells. Mutations in AIRE gene underlie autoimmune polyendocrinopathy
- *Receptor editing:* when developing B cells strongly recognize self antigens in bone marrow, amny of the cells reactivate machinery of antigen receptor gene rearrangement and begin to express new antigen receptors not specific for self antigen.
If receptor editing does not occur, self-reactive cells undergo apoptosis
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Peripheral tolerance- concepts
* *1. Anergy: Lymphocytes that recognize self antigens may be rendered functionally unresponsive, a phenomenon called anergy**
- Two signals are needed for antigen-specific T cell activation (Antigen in association with MHC, and costimulatory molecules (CD28 from APCs)
- Costimulatory molecules are weakly or not expressed on resting dendritic cells, so if they encounter self-reactive T cells, it may lead to anergy.
- Inhibitory receptors (CTLA-4, PD-1) that are homologous to CD28, but have opposite functions, may bind to B7 molecules instead of CD28, when B7 levels are low (when self-antigens are being presented)
Anergy also affects mature B cells in peripheral tissues, especially in absence of helper T cells; B cells cannot respond to to antigens
* *2. Suppression by regulatory T cells: *Regulatory T cells* function to prevent immune reactions against self antigens**
- These develop in the thymus as a result of self-antigen recognition
- Best defined Treg cells have a lot of CD25 (alpha-chain of IL-2 receptor) and FOXP3 (transcription factor)
- FOXP3 mutations result in severe autoimmunity in humans and mice (systemic autoimmune disease called IPEX)
- CD25 mutations may cause multiple sclerosis
- Treg inhibition mediated by IL-10, TGF-B)
- **Regulatory T cells may play a role in acceptance of the fetus**
* *3. Deletion by apoptosis: T cells that recognize self antigens may receive signals that promote their death by** **apoptosis via 2 methods**
(1) Self-reactive T cells may express a pro-apoptotic member of Bcl family (**BIM**) iwthout anti-apoptotic members, causing apoptosis via the mitochondrial pathway
(2) Lymphocytes express death receptor (Fas, CD95); FasL is expressed mainly on activated T lymphocytes. If self antigens engage self-reactive T cell receptors, Fas and FasL are co-expressed, leading to Fas-mediated apoptosis
- Fas/FasL mutants may develop *autoimmune lymphoproliferative syndrome (ALPS)*, which resembles human SLE
Testis, eyes, brain, are all separate from blood and lymph, and are called *immune-priveleged sites*, self-antigens in these sites are ignored by immune system
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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.
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Mechanisms of autoimmunity: General Principles
**Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes.**
The susceptibility genes and environmental triggers induce a number of changes that contribute to the development of autimmunity:
* *1. Defective tolerance or regulation
2. Abnormal display of self-antigens
3. Inflammation or an initial innate immune response**
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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.
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Role of susceptibility genes in autoimmunity
**Most autoimmune diseases are complex multigenic disorders. There is a genetic component in autoimmunity. Incidence is greater in twins of affected individuals than in general population, even greater in monozygotic twins.**
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Association of HLA (MHC) genes and non-HLA genes with autoimmune disease
**Among the genes known to be associated with autoimmunity, the greatest contribution is that of HLA genes**.
Multiple non-MHC genes are associated with various autoimmune diseases
PTPN22 - protein tyrosine phosphatase - rheumatoid arhtritis, type 1 diabetes, several others
NOD2 - chron disease
IL-2 receptor (CD25) gene - multiple sclerosis, others
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Role of infections in autoimmunity
* *Autoimmune reactions may be triggered by infections via two hypothesized mechanisms:**
1. infections may upregulate expression of costimulators on APCs; if they present self-antigens, this may cause a breakdown in anergy
2. Some microbes may express antigens that have same amino acid sequences as self-antigens (*molecular mimicry*)
**Infections may protect against some autoimmune diseases** **due to unclear mechanisms**. Possible: IL-2 production during infections promotes Treg production
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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).
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KEY CONCEPTS: Immunologic tolerance and autoimmunity
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General features of autoimmune diseases
* *1. Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often progressive.**
- many intrinsic amplification loops in the immune system
- *epitope spreading:* immune response against a self antigen causes tissue damage, releasing other antigens, resulting in activation of lymphocytes by new epitopes
* *2. The clinical and pathologic manifestations of an autoimmune disease are determined by teh nature of the underlying immune response.**
- some are caused by autoantibodies
- most caused by excessive Th1, Th17 responses
- some due to CTL cell-killing
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Systemic Lupus Erythematosus (SLE) - definition
**SLE is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues.**
May be acute or insidious in onset, and is typically a chronic, remitting and relapsing, often febrile, illness. Injury to skin, joints, kidney, serosa, are prominent, but any organs can be affected.
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Spectrum of autoantibodies in SLE
**The hallmark of SLE is the production of autoantibodies.**
* *Antinuclear antibodies are directed against nuclear antigens and can be grouped into 4 categories:**
(1) antibodies to DNA
(2) antibodies to histones
(3) antibodies to nonhistone proteins bound to RNA
(4) antibodies to nucleolar antigens
Indirect immunofluorescence is the most common method for detecting ANAs, with four basic staining patterns:
(1) homogeneous/diffuse nuclear staining - chromatin, histones, or dsDNA stained
(2) Rim/peripheral staining - dsDNA, some nuclear envelope proteins
(3) Speckled pattern - very common, least specific, non-DNA constituents stained
(4) Nucleolar pattern - RNA stained
(5) Centromeric
Combinations of patterns are frequent because many autoantibodies may be present
**Antibodies to dsDNA and Smith antigen are diagnostic of SLE**
Other antibodies can be present in SLE, and directed toward RBCs, platelets, lymphocytes, phospholipid-protein complexes
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Etiology and pathogenesis of SLE
**The fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance; both genetic and environmental factors play a role.**
Genetic factors - Genetically complex disease with MHC and non-MHC genes contributing
- possible inherited deficiencies in complement components
Immunologic factors:
- **Failure of self-tolerance in B cells:** Defective elimination of self-reactive B cells in bone marrow or defects in peripheral tolerance
- **CD4+ helper T cells specific for nucleosomal antigen escape tolerance and contribute to production of high-affinity pathogenic autoantibodies**
- **TLR engagement by nuclear DNA and RNA in immune complexes may activate B lymphocytes
- Type I interferons play a role in lymph activation in SLE**
Environmental factors:
* *- exposure to UV light exacerbates disease
- gender bias - females more than males
- Drugs (hydralazine, procainamide, D-penicillamine)**
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Mechanisms of Tissue Injury with SLE
* *1. Most of the systemic lesions are caused by immune complexes (Type III hypersensitivity)**
- DNA-anti-DNA complexes detected in glomeruli and small vessels
* *2. Autoantibodies specific for RBCs, WBCs, platelets opsonize these cells and promote their phagocytosis and lysis**
- if cell nuclei are exposed, ANAs can bind to them, forming LE bodies which get phagocytized by LE cells
* *3. Antiphospholipid antibody syndrome**
- patients with antiphospholipid antibodies may develop thromboses and miscarriaages and focal cerebral/ocular ischemia
- referred to as *secondary antiphospholipid antibody syndrome*
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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.
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MORPHOLOGY - SLE
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Chronic Discoid Lupus Erythematosus
Skin manifestations mimic SLE, but systemic manifestations are rare.
Skin plaques, edema, erythema, scaliness, follicular plugging, skin atrophy
Face and scalp are usually affected
Occurs in dogs
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Sjogren-like syndrome
Systemic autoimmune disease that causes KCS, xerostomia, lymphplasmacytic adenitis in dogs and cats
Dogs usually have hypergammaglobulinemia and occasionally have ANAs and rheumatoid factors.
Clinical signs:
- Adult-onset conjunctivits and keratitis
- Gingivitis and stomatitis
- Xerostomia and dysphagia
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Inflammatory myopathies (especially dermatomyositis)
Four distinct disorders in domestic species:
1. Masticatory muscle myositis
2. Generalized inflammatory myositis
3. Dermatomyositis
4. Extraocular myostitis
Dermatomyositis:
- Inflammatory disease of skin, muscles, vessels, affecting young dogs (usually 2-6 months)
- Higher incidence in collies and Shetland sheepdogs, is considered familial in these
_Lesions:_
- Alopecia, erythematous dermatitis on face, ears, bony prominences of extremities
- Erosions and ulcers early on, then scarring and pigmentary changes chronically
- Histo: necrotic basal and follicular epithelial clels, mixed inflammation +/- ulceration and fibrosis
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Vasculitis
Definition, example
**Inflammation of walls of blood vessels.**
Most often seen as part of an underlying process (e.g. infectious, neoplastic) or as an adverse drug / vaccine reaction (i.e. type III hypersensitivity)
Juvenile polyarteritis (a.k.a. beagle pain syndrome, SRMA): idiopathic febrile disease causing systemic necrotizing vasculitis primarily in young (4-10 months) beagles.
_Clinical signs and lab findings_:
- Fever
- anorexia
- Hunched stance
- Cervical pain
- Neutrophilia, nonregenerative anemia, hypoalbuminemia
- CSF: neutrophilic pleocytosis with slight inc. in protein
_Lesions:_
- Severe necrotizing vasculitis and perivasculitis with thrombosis of small vessels in leptomeninges of cervical spinal cord, cranial mediastinum, and heart are commonly seen
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Immunodeficiency syndromes:
Definition, Categories
They occur when there is a failure of the immune system to protect the host from infectious organisms or cancer development
Primary immunodeficiency - caused by a genetic defect in a component of the immune system; the disease may manifest at birth or later in life
Secondary immunodeficiency: Caused by acquired loss of immune function (e.g. complications from infections, malnutrition, againg, irradiation, chemo)
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Primary immunodeficiencies
Genetically determined, and affect innate and/or cellular or humoral branches of adaptive immunity.
Most primary immunodeficiencies are detected between 6 months adn 2 years due to recurrent infections.
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Primary immunodeficiencies of innate (nonspecific) immunity:
Deficiencies of the complement system
\> 30 soluble and cell-bound proteins that influence immune and inflammatory responses make up the complement system.
In humans, deficiencies in most of the components and 2 of the inhibitors have been identified (C2 deficiency is most common, but classical pathway deficiencies are usually subclinical)
An autosomal recessive trait causing C3 deficiency described in Brittany spaniels, and causes susceptibility to infections and type 1 membranoproliferative glomerulonephritis
Factor H deficiency (from alternative pathway) in Norwegian Yorkshire pigs - type II MP GN
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Primary immunodeficiencies of innate (nonspecific) immunity:
Chediak-Higashi Syndrome
Inherited disease caused by defective lysosomes, melanosomes, platelet- dense granules, and cytolytic granules, described in cats, cattle, killer whales, beige mice, rats, Aleutian minks, and humans.
Clinical manifestations:
- Hypopigmentation
- Bleeding tendency
- Ocular abnormalities
- Recurrent infections
Hallmarks of disease:
- Enlarged granules within melanocytes, neutrophils, eosinophils, monocytes
Neutrophil and NK functionimpaired
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Primary immunodeficiencies of innate (nonspecific) immunity:
Leukocyte adhesion deficiency
Primary immunodeficiency disease characterized by inability of leukocytes to migrate from circulation into sites of inflammation --\> recurrent bacterial infections
Best described in humans, in bovine (BLAD), and in canines (CLAD) - defect is inherited as an autosomal recessive trait.
Irish setter dogs and Holstein cattle most commonly affected.
Hallmark of disease: profound neutrophilia
Irish setters often get omphalophlebitis right after birth and by 4 months, have gingivitis, osteomyelitis, lymphadenopathy (similar in calves)
Dogs usually die by 6 months from infections, and cattle by 7 months
Molecular basis:
Defective b2-integrin expression
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Primary immunodeficiencies of adaptive (specific) immunity:
Defects in lymphocyte maturation:
Severe Combined Immunodeficiency disease (SCID)
Family of genetic defects that have deficiencies in both humoral and cell-mediated immunity
Extreme form: defect in common lymphoid stem cell
More common: SCID affects either T lymphs or B+T lymphs; best characterized in humans, mice, dogs, horses
Most common infections are often viral and fungal secondary to SCID.
SCID in horses:
- Autosomal recessive disorder in Arabians, causing a severe lymphopenia
- Neonates have IgM deficiencies before getting colostrum, and agammaglobulinemia develops after catabolism of colostral antibodies, followed by recurrent infections (Pneumocystis, cryptosporidium, others), thymic hypoplasia
- Defect in gene encoding catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) on chromosome 9
SCID in dogs:
- First described as X-linked (XSCID) in Basset hounds
- Lymphopenia with increased B lymphs and almost no T lymphs
- at 6-8 weeks, as maternal Abs decline, recurrent skin/resp/GI infections occur.
- Hypogammaglobulinemic with low IgG and IgA levels
- Dogs rarely live to 4 months due to frequent viral infections
- Hypoplastic lymphoid tissue
- Mutation in gamma subunit of IL-2, IL-4, IL-7, IL-9, IL-15 receptors
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Primary immunodeficiencies of adaptive (specific) immunity:
Defects in lymphocyte maturation:
Agammaglobulinemia
Primary immunodeficiency characterized by inability to produce immunoglobulins and an absence of mature B lymphs and plasma cells
Described in Thoroughbred, QH, Standardbred horses
All cases have been males to date, suggesting that it is X-linked, like in humans
Absence of plasma cells, primary follicles, germinal centers in LNs
Horses get extracellular bacterial infections of joints and respiratory system
BTK gene mutation in humans, which is on X chromsome and encodes tyrosine kinase that causes B-lymphocyte development
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Primary immunodeficiencies of adaptive (specific) immunity:
Defects in lymphocyte maturation:
Thymic hypoplasia (Digeorge Syndrome)
Represents a number of immunodeficiency diseases characterized by a failure to develop a functional thymus, resulting in T-lymphcoyte deficiency.
Homozygous mice for the trait nu are hairless and have developmental arrest of the thymus, defective cell-mediated responses, and lack antibody production
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Primary immunodeficiencies of adaptive (specific) immunity:
Defects in lymphocyte activation and function:
Common variable immunodeficiency
**This relatively frequent, but poorly defined entity encompasses a heterogeneous group of disorders in which the common feature is hypogammaglobulinemia, generally affecting all the antibody classes, but sometimes only IgG**.
Attributed to an intrinsic B-lymphocyte defect, causing inability to produce antibodies.
Described in a litter of miniature Dachshund dogs, with absence of B-lymphocytes in lymphoid tissue and little to no serum Igs.
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Primary immunodeficiencies of adaptive (specific) immunity:
Defects in lymphocyte activation and function:
Selective immunoglobulin deficiencies
**Selective deficiencies are represented by a number of diseases characterized by a deficiency of an individual class of immunoglobulin.**
Described in horses and dogs
Most common forms are IgM deficiency and IgA deficiency. B-lymphocyte numbrs and other classes of Igs are normal.
May not result in clinical signs until maternal antibodies are degraded.
Most affected horses get IgM deficiency and die by 10 months.
Selective IgA deficiency described in GSD, Shar-Pei, Irish setter, beagle --\> resp/GI/skin infections
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Amyloidosis definition
**Amyloidosis is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise.**
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Amyloidosis - chemical nature
Amyloid contains 95% fibrillar proteins and 5% P component and other glycoproteins.
15 biochemically distinct forms of amyloid in humans; 3 most common:
1. amyloid light chain (AL), derived from Ig light chains of plasma cells (most consist of lambda-light chains)
2. Amyloid associated (AA), derived from acute phase protein SAA
3. A-beta amyloid, derived from amyloid precursor protein (APP) (associated with neurodegenerative disease in dog brain)
Islet amyloid, dervied from islet amyloid polypeptide (IAPP) from beta cells of the endocrine pancreas, affects the feline pancreas
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Amyloidosis - classification
Subclassified in several ways (localized vs. systemic, primary vs. secondary, more specific causes)
1. Primary amyloidosis (AL), associated with immunocyte dyscrasia
- Most common type of amyloidosis
- Most common immunocyte dyscrasia associated with AL amyloidosis is plasma cell neoplasia
- May be recognized with SPE - monoclonal gammopathy
- Some cases only have the light chain component (i.e. Bence Jones), most commonly is the lambda light chain
2. Reactive systemic amyloidosis (AA), associated with chronic inflammation
- Recognized in most species
3. Familial amyloidosis (AA)
- Hereditary in Shar Peis, Abyssinian cats, Siamese cats
- Various organ systems affected (commonly in kdiney - glomerular in abyssinian cats, medullary interstitium in shar peis)
4. Localized amyloidosis
- Present in calcifying epithelial odontogenic tumors of dogs and cats
5. Endocrine amyloidosis (IAPP amyloid)
- Cats, nonhuman primates, humans can get pancreatic amyloidosis, which may lead to type 2 DM
6. Amyloid of aging (most commonly A-beta type)
- Can occur in numerous organ systems
- Old dogs can develop neurodegenerative changes
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Amyloidosis - pathogenesis
**Amyloid deposition occurs due to abnormal folding of pathogenic proteins, deposited extracellularly as fibrils organized into b-pleated sheets.**
Two general categories of amyloidgenic proteins:
(1) Normal proteins that have an inherent tendency to misfold
(2) Abnormal proteins from genetic mutations that are unstable
When normal degradative processes of macrophages and other cells are inadequate, amyloidosis occurs.
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Pathogenesis of amyloidosis, showing the proposed mechanisms underlying deposition of the major forms of amyloid fibrils.
