Immunopathology

Chapter 4 Immunopathology



Zoran Gatalica, MD, DSc




1 What are the main cells of the immune system?



image Lymphocytes

image T lymphocytes

image B lymphocytes

image Natural killer cells

image Macrophages

image Dendritic cells

Neutrophils, eosinophils, basophils, and platelets found in the blood are an important part of the body defense system but are not directly involved in recognition of foreign (nonself) stimuli and antigens, which is the primary function and characteristic of the cells of the immune system.



2 List key facts about T lymphocytes



image T lymphocytes are typically found in the following locations:
image Paracortical areas of lymph nodes

image Periarteriolar sheaths of the spleen

image Thymus

image Bone marrow and peripheral blood

image T lymphocytes account for 60% to 70% of circulating lymphocytes in the blood.

image The specific surface antigen is antigen-specific T-cell receptor (TCR), which can be composed of αβ (95% of T cells) or γσ heterodimers. Each T cell has a unique TCR, reflecting a unique rearrangement of the genes (marker of clonality).

image The common surface marker present on all T lymphocytes is nonvariable CD3 protein (pan T-cell marker).

image There is functional diversity of T-cell populations; CD4+ helper/inducer cells constitute approximately 60% of mature T lymphocytes, and CD8+ suppressor/cytotoxic cells constitute approximately 30% of mature T lymphocytes. Furthermore, CD4+ cells differ in their ability to secrete cytokines: The TH1 subset secretes IL-2 and IFN-γ, whereas TH2 secretes IL-4 and IL-5.


3 List key features of B lymphocytes



image B lymphocytes are typically found in the following locations:
image Superficial cortex of lymph nodes

image Germinal centers and mantle zone of stimulated lymph nodes

image Follicles of the white pulp of the spleen

image Mucosa-associated lymphoid system (MALT) in intestines and the respiratory tract

image Bone marrow and peripheral blood

image B lymphocytes constitute 10% to 20% of circulating lymphocytes in the blood.

image Antigen-specific surface immunoglobulin M (IgM) is the consequence of the unique gene rearrangements and a marker of B-cell clonality.

image Two more nonvariable transmembrane proteins (Igα and Igβ) form a heterodimer that is a part of the B-cell receptor complex.

image On antigenic stimulation, B cells form plasma cells that secrete antigen-specific immunoglobulins.


4 List key features of natural killer (NK) cells



image NK cells constitute approximately 10% to 15% of circulating lymphocytes.

image They are CD3 negative and do not rearrange the CD3 gene but do express some surface T-cell markers. They express receptors for Fc of IgG (also known as CD16), which enables them to lyse IgG-coated target cells.

image They can kill a variety of virus-infected cells and some tumor cells without prior sensitization (i.e., “natural” killer). NK cells express inhibiting receptors for class I major histocompatability complex (MHC) molecules present on all nucleated cells. If a virus or a neoplastic transformation altered the expression of MHC class I molecules, the inhibition is interrupted and the NK cell attacks the altered cell (causing cell lysis).


5 What is the main function of macrophages in the immune response?


Macrophages belong to the class of antigen presenting cells (APCs), crucial for the activation of T lymphocytes. Macrophages take up the antigen, process it, and present it to T cells.



6 What are dendritic cells?


Dendritic cells are APCs found in the germinal follicles (follicular dendritic cells), interstitium of many organs (interdigitating dendritic cells), and the skin (Langerhans cells).



7 List key features of cytokines



image Cytokines are soluble signaling molecules secreted by a variety of cells, both of the immune and the nonimmune system.

image They can act on the same cell that secreted them (autocrine effect), on the cells in close proximity (paracrine effect), or on remote cells after being transported through the bloodstream (endocrine effect).

image The best-known cytokines are interferons, interleukins (ILs), tumor necrosis factor, chemokines (chemoattractors), and colony-stimulating factors (hematopoietic growth factors).


8 What are the characteristics of histocompatibility antigens?


They bind processed foreign proteins (e.g., viral particles during cell infection and phagocytized material) and are involved in presenting them on the cell surface to T cells.


Class I antigens are expressed on all nucleated cells and are encoded by three closely linked gene loci (HLA-A, HLA-B, and HLA-C). Foreign protein (e.g., viral particles synthesized within the cell) is associated with MHC class I protein and transported to the cell surface, where it is recognized by CD8+ cytotoxic T cells bearing TCR specific for the antigen peptide.


Class II antigen (HLA-DP, HLA-DQ, and HLA-DR) expression is restricted to APCs (macrophages and dendritic cells); they bind phagocytized antigens and present them on their surface, where they are recognized by CD4+ helper T lymphocytes.


An association of certain diseases and specific HLA types (higher relative risk of developing certain disease) has been noticed. This may be because of the close proximity of HLA genes and the disease-causing gene on chromosome 6 or because of the type of HLA (so-called haplotype).



9 How are the antigens classified?



image Exogenous (e.g., dust, pollens, chemicals)

image Endogenous, formed within the body of the same individual (autologous) or genetically different individual of the same species (homologous)


10 What is the pathogenesis of hypersensitivity reactions?


In certain individuals, repeated exposure to a specific antigen leads to adverse reactions (hypersensitivity) rather than an induction of a protective immune response (immunity). Several pathogenetic mechanisms underlie tissue destruction in hypersensitivity:


image Release of vasoactive and spasmogenic mediators of inflammation (type I)

image Binding of antibodies to the antigens on the cell surface, predisposing them to lysis of phagocytosis (type II)

image Formation of antigen–antibody complexes capable of activation of the complement system (type III)

image Sensitization of T lymphocytes after reaction with antigen leading to granulomatous inflammation initiated by CD4+ lymphocyte sensitization or leading to CD8+ killing of antigen-bearing cells (both examples of type IV hypersensitivity reaction)


11 What are the characteristics of type I hypersensitivity (anaphylactic) reactions?



image Develop rapidly (within minutes) following exposure to the antigen in a previously sensitized individual

image Based on a mast cell participation

image Mediated by IgE in most instances


12 Are the type I hypersensitivity reactions localized or systemic?


Type I hypersensitivity reaction may cause a localized or a systemic reaction.


image Localized reaction: If the allergen is confined to the site of contact, localized edema and inflammation typically develop (e.g., hives and rhinitis). This reaction causes only minor discomfort, but it may also be life threatening if it involves the larynx or the bronchial tree (e.g., bronchial asthma).

image Systemic reaction: A life-threatening anaphylactic shock may develop, especially if the antigen was introduced intravenously (e.g., antibiotic).


13 What is the pathogenesis of localized type I hypersensitivity reactions?


These reactions involve the interaction of three cell types:


image B cells: Virgin B cells stimulated by antigen (allergen) transform into IgE-secreting plasma cells.

image TH2 lymphocytes: Helper T lymphocytes produce IL-4, which is necessary for stimulation of IgE-secreting B cells.

image Mast cells: These cells bind IgE to their surface and act as effector cells.

First exposure leads to a sensitization and priming of the T and B cells, which interact and produce IgE that binds to the surface of mast cells in tissues. Upon second exposure to the same antigen, cross-linking of IgE on the mast cells occurs. Cell surface changes stimulate two sets of reactions (Fig. 4-1).


image Immediate reaction: This involves a rapid release of mediators stored in mast cell granules.

image Delayed reaction: This reaction is mediated by substances that need to be synthesized, and their release occurs several hours after the initiation of the immune reaction.

image

Figure 4-1 Type I hypersensitivity (anaphylactic) reaction. Binding of immunoglobulin E (IgE) and antigen to the surface of mast cells leads to an immediate release of preformed mediators stored in the cytoplasmic granules. The synthesis of other mediators requires several hours and, accordingly, such mediators are released later. PAF, Platelet-activating factor.



14 What occurs during the immediate degranulation of mast cells?


Antigen-triggered degranulation of mast cells leads to a release of preformed (primary) mediators of inflammation:


image Biogenic amines: Histamine, the primary mediator of this group, will increase vascular permeability (→ edema) and stimulate smooth muscle contraction (bronchospasm) and secretion of mucus or gastric juices.

image Enzymes: Hydrolytic enzymes (e.g., chymase and tryptase) contribute to inflammation by activating kinins and the complement system. Fragments of complement proteins have a chemotactic action and recruit other cells to the site of inflammation.

image Proteoglycans: The most important is heparin, which has an anticoagulant action.


15 Which mediators are released from mast cells in a delayed manner?


These mediators, known as secondary mediators and released 6 to 12 hours later, include:


image Lipid-derived mediators: Antigen binding to mast cells triggers an activation of phospholipase A2 that generates arachidonic acid from intracellular lipids. Arachidonic acid is further metabolized into leukotrienes and prostaglandins. Platelet-activating factor (PAF) is also formed.

image Cytokines: This response is characterized by the recruitment of inflammatory cells (neutrophils and eosinophils) that sustain the inflammation, causing further damage in the affected tissue.


16 What are the symptoms associated with type I hypersensitivity reactions?


The symptoms depend on the route of exposure, dose of antigen, and the target organ sensitivity (Fig. 4-2).


image Systemic allergen presentation: Typically this reaction occurs upon injection of drugs, hormones, or antisera into a previously sensitized person. Clinically, an anaphylactic shock develops, which is characterized by hypotension due to widespread vascular dilatation, widespread edema, difficulty breathing due to laryngospasm, laryngeal and pulmonary edema, and cardiac dysrhythmia.

image Localized reactions: Antigen entering the body through the skin, by inhalation, or through ingestion evokes a reaction usually limited to one organ system.
image Upper respiratory tract reactions: Seasonal upper respiratory allergies caused by pollens (>10μm) evoke hay fever. Similar but prolonged allergic rhinitis may result from sensitization to dust mites. In both instances, there is nasal congestion, watery discharge, itching, sneezing, and cough.

image Gastrointestinal reactions: Ingestion of allergens may lead to diarrhea, malabsorption syndrome, and protein-losing enteropathy. Massive hypoproteinemia may even cause shock.

image Bronchopulmonary reactions: Asthma is an example of hypersensitivity of small airways to inhaled allergens. It presents with bronchospasm causing wheezing, hypersecretion of mucus, and coughing. Death due to asphyxia may result from extreme bronchoconstriction and plugging of bronchi with mucus (status asthmaticus).

image Skin reactions: Atopic dermatitis, a common disease of childhood, is caused by prolonged exposure to and sensitization by foreign antigens.

image

Figure 4-2 Type I hypersensitivity reactions. Local manifestations of allergic reactions include itching, angioedema (swelling caused by exudation), edema of the larynx, urticaria (hives), and bronchospasm (constriction of airways in the lungs). Hypotension and dysrhythmias (irregular heartbeat) are typically found in anaphylactic shock. Gastrointestinal symptoms are due to food allergy.


(From McCance K, Huether S: Pathophysiology: The Biologic Basis for Disease in Adults and Children, 5th ed. St. Louis, Mosby, 2006, p. 254.)



17 What are the characteristics of type II hypersensitivity (cytolytic) reactions?


Antigen is present on the surface of the target cell. It may be intrinsic antigen (e.g., Rh D blood antigen) or antigen adsorbed on the cell surface from the environment (e.g., drugs acting as haptens). The antibody interaction with the antigen elicits three reactions (Fig. 4-3):


image Complement-activated cell lysis: Binding of antibody (primarily IgM) to the antigen on the cell surface leads to an activation of complement-activated cell lysis and the formation of the cytolytic membrane attack complex (MAC), which destroys cells (e.g., acute hemolytic transfusion reaction).
image Antibody-dependent cell-mediated cytotoxicity (ADCC): Binding of low-density (primarily IgG) antibodies that act as opsonins is followed by phagocytosis of damaged cells. ADCC typically mediates autoimmune hemolytic anemia and thrombocytopenia.

image Antibody-mediated cell dysfunction: Binding of stimulatory antibodies to receptors for thyroid-stimulating hormone (TSH) on thyroid cells may stimulate hypersecretion of thyroid hormones in Graves disease. Binding of antiacetylcholine receptor antibodies at the neuromuscular junction may block nerve transmission and the cause of muscle weakness in myasthenia gravis.

image

Figure 4-3 Type II hypersensitivity (antibody-mediated) reactions. A, Complement-mediated cell lysis. B, Antibody-dependent cell-mediated cytotoxicity. C, Antibody-mediated cell dysfunction.



18 List important diseases caused by type II hypersensitivity cytotoxic reactions



image Transfusion reaction: This is caused by a mismatched blood transfusion. An infusion of blood of an A blood group donor into a B blood group recipient will result in a massive hemolytic reaction mediated by the natural anti-A blood group antigen in the recipient.

image Hemolytic disease of the newborn (erythroblastosis fetalis): This reaction occurs transplacentally and is mediated by maternal IgG antibodies to the fetal Rh+ positive red blood cells (RBCs). It occurs only in Rh− mothers who have been immunized to Rh blood group antigen during the first pregnancy by an Rh+ fetus.

image Autoimmune hemolytic anemia: This disease results from the production of anti-RBC antibodies that bind to RBC and cause hemolysis. The causes of such an immune reaction are not known.

image Pemphigus vulgaris: This blistering skin disease is caused by antibodies to the proteins forming the intercellular junctions (desmosomes) of the epidermis.

image Goodpasture syndrome: This pulmonary–renal disease is caused by antibodies that react with type IV collagen in the glomerular and pulmonary vascular basement membranes. One could call these antibodies cytotoxic, but the term membranotoxic seems more appropriate.


19 What are the characteristics of immune complex–mediated hypersensitivity (type III) reactions?



image Binding of antibody to the antigen forms complexes that are not cleared by the reticuloendothelial system but instead are deposited in tissues where they elicit an inflammatory reaction through activation of complement (Fig. 4-4).

image Complexes may be formed locally in the tissue or in the circulation and then deposited in various tissues. Either way, aggregated Fc regions of IgG antibodies activate the complement pathway, leading to increased vascular permeability, activation of neutrophils, and tissue necrosis.

image Antigens capable of inducing type III hypersensitivity reaction may be exogenous (e.g., streptococcal antigens, hepatitis B virus, and heroin) or endogenous (e.g., immunoglobulins and nuclear antigens).

image

Figure 4-4 Type III (immune complex–mediated) hypersensitivity reaction. The deposition on immune complexes leads to the activation of complement and subsequent influx of inflammatory cells and destruction of the vessel wall. PMN, polymorphonuclear leukocyte.



20 List the most important diseases caused by type III hypersensitivity reaction



image Systemic lupus erythematosus (SLE): This disease is caused by circulating immune complexes that deposit in many organs, most often the skin, joints, and kidneys. Circulating blood cells are also often affected, resulting in anemia, leukopenia, and thrombocytopenia.

image Polyarteritis nodosa: This disease typically affects medium-sized arteries of internal organs, skin, eye, or peripheral nerves in an unpredictable manner.

image Acute poststreptococcal glomerulonephritis: This kidney disease typically follows a streptococcal throat infection and the formation of circulating antistreptococcal antibodies, which deposit in the glomerular basement membranes.

image Membranous nephropathy: In some forms of this immune-mediated glomerulopathy, there are circulating antigen-antibody complexes that deposit on the epithelial side of the glomerular basement membrane. The disease typically presents as nephrotic syndrome and massive proteinuria.

image Serum sickness: Injection of foreign serums may cause the formation of circulating immune complexes that are deposited in many organs. Most often it presents with a skin rash.
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Related posts:

  1. Cell Pathology
  2. Inflammation and Repair
  3. Bones and Joints
  4. The Hematopoietic and Lymphoid Systems

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Jul 23, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Immunopathology

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