Dr. Joselli c. Rueda-cu
July 26- 28, 2011
PATHOLOGY
00
Immunopathology 1
The Immune system
o Vital for survival that protects us from the environment filled with deadly microbes and infectious pathogens Immunopathologic States
o Immunodeficiency
Renders and individual an easy prey of infections and tumours
o Hyperactive
May cause fatal disease, as in the case of an overwhelming allergic reaction
Hypersensitivity diseases o Autoimmune
Immune reaction against self
Immune system loses its normal capacity to distinguish self from non-self
Fig 1. Innate and Adaptive Immunity
A. Innate (Natural/Native) Immunity ̶ First line of defense
Recognizes microbes, protection against infections ̶ Present before infection
̶ Components:
a. Epithelial Barriers
Mechanical barriers against entry of microbes from external environment
Produce anti-microbial molecule such as defensins and lymphocytes
b. Phagocytic Cells
Mostly neutrophils and macrophages
One of two cellular reactions of innate immunity that causes inflammation
If absent, a person’s immune system is congenitally impaired
c. Dendritic Cells
Produce type I interferons which inhibit viral infection and replication
One of two important cellular reactions of innate immunity as anti-viral defense together with NK cells
d. Natural Killer Cells
Protect against viruses and intracellular bacteria e. Plasma Proteins
Complement system proteins Lysis f. Lung Surfactant
Lowers surface tension of the lungs Component of innate immunity
Provides protection against inhaled microbes. B. Adaptive (Acquired/Specific) Immunity
̶ Stimulated by antigens/ microbes
Antigens (Ag) – Foreign bodies accessed by the immune system as substance to be destroyed. B lymphocytes – Most responsible for destruction of
the antigen by maturing to a plasma cell then releasing antibodies
̶ Recognition of microbial and non-microbial substances ̶ Develops after exposure to microbes
̶ More powerful than innate immunity in combating infections
Component of both Innate and Adaptive Immunity o Cause cell lysis
o In Innate Immunity:
It is activated by binding to microbes
Uses Alternate and Lectin pathways
Mannose-binding Lectin and C-reactive protein
Coat microbes for phagocytosis and complement activation
C reactive protein indication of an inflammatory process
o In Adaptive Immunity:
Activated by binding to antibodies using Classical pathways
Thymus derived cellular immune response 60-70% of lymphocytes
Anatomic residence: a. Thymus
b. Found in paracortical areas of lymph nodes c. Periarteriolar sheaths of the spleen
Contain T-cell receptors which bind Major Histocompatibility Complex (MHC) molecules on the surface of Antigen-presenting cells
The Complement System
T-Lymphocytes
Cell and Tissues of the Immune System
Mechanisms of Protection
General Features of the Immune System
THE IMMUNE SYSTEM
I. The Immune System a. General Features b. Mechanisms of Protection c. Cellular Components d. Categories of the Immune
System e. MHC Molecules II. Hypersensitivity Reactions
a. Type I b. Type II c. Type III d. Type IV III. Transplant Rejections
SECTION B
UERMMMC Class 2014
Pathology 2 | 10
Subsets:1. Cytotoxic T cells
̶ 70% to 80% of circulating blood lymphocytes ̶ Majority of the T-lymphocytes
̶ Express CD8+ surface receptors ̶ Destroy infected and tumour cells 2. Helper T cells
̶ Help/ facilitate in microbial destruction ̶ Express CD4+ surface receptors ̶ Contain T-cell receptors (TCRs) which:
Are polymorphic antigen-binding molecules
Bind antigens associated with MHC on other cells
Analogous to surface immunoglobulins (Ig) of B cells
Can rearrange their genes to respond to antigenic stimuli
3. Suppressor T cells
̶ Express pan T-markers (pan- means everything/ a lot) including CD2, CD3 and CD5
Note:
CD3 are invariant molecules (meaning, it’s identical in all T cells) which bind to the TCR forming the TCR complex Signal transduction pathways in T cells once antigen is presented in these complexes T cell responses.
TCRs are Polymorphic Ag-binding molecules, analogous to
surface Ig that binds Ag associated with MHC on other cells.
Bone marrow derived humoral immune response 10-20% of lymphocytes
Anatomic residence: a. Bone marrow b. Blood
c. Cortex of lymph nodes and germinal centers d. Splenic white pulp
e. Lymphoid follicles
Responses to protein antigens require help from CD4+ T cells Engages CD40, necessary for B cell maturation and secretion of IgG, IgA and IgE antibody
CD40 – Member of the Tumor Necrotic Factor (TNF)-receptor family and by cytokines activated helper T lymphocytes express CD40 ligand, which specifically binds to CD40 expressed on B cells
B cells express several molecules on their surface (just like TCR’s in T cells) responsible for response activation (ex. CD40, Fc receptors, CD21 etc.)
o CD4+ T cells engage CD40, a member of the TNF receptor family
o CD40 is necessary for B cell maturation and the secretion of IgA, IgE and IgG antibodies
o Activated helper T lymphocytes express the CD40 ligand (CD40L), which specifically binds to CD40 expressed on B cells.
o Mutations in the gene encoding CD40 ligands may result to X-linked hyper-IgM syndrome No IgG production o The 3 types of mutation in CD40 ligands are
Translocation, Amplification and Point Mutation. (TAP)
Note:
Igα and Igβ are 2 invariant proteins of B cell antigen
receptor complex (much like CD3 of T cells) needed for signal transduction pathways B cell responses.
Fc receptors are proteins found on the surface of cells that contribute to the protective functions of the immune system.
Second line of defense
Seen in cellular immune response
They can serve as APCs and they can be Activated Activated Macrophages
o Express MHC class II receptor
o Cytokine activation of CD4+ cells enhances microbicidal properties of macrophages and augments their ability to kill tumor cells
Antigen Presenting Cell
o Induction of cell mediated immune response
Process the antigens in phagocytosed microbes and present peptide fragments to T cells
T-cells become more sensitive to the bacteria that the macrophage caries
T-cells then produce cytokines that enable macrophages to destroy the bacteria In Effector phase of humoral immunity
o They phagocytose microbes opsonised (Making microbes
more palatable/ edible by macrophage) by IgG or C3b
MLE Q: Only cytokines are involved, no antibodiesNote:
According to Dr. Cu – Macrophage (when presenting antigens to T cells) tells T-Lymphocytes “I’m carrying
something I cannot destroy, will you help me?”
Fig 2. The role of dendritic cells in capturing microbial antigens from epithelia and
transporting them to regional lymph nodes. Immature DC (ex. Langerhans cell in epithelia) respond to microbes and are activated Migrate to lymph nodes via lymphatic vessels DC recruited to T- cell zones of lymphoid organs to function as APCs to T cells. Please refer to Fig. 6-10 p. 194 of Robbin’s for a clearer image.
Resident phagocytes
Found under the lining epithelium which is the most common entry site of antigens
10-20% of circulating peripheral lymphocytes
Most important antigen presenting cells for initiating primary immune response against protein antigens
Location: (
MLE Q)o Under epithelia, the most common entry site of antigens and interstitial of all tissues where Ag maybe produced
Dendritic Cells
Macrophages
Types:
1. Interdigitating dendritic cells/ simply dendritic cells ̶ Most important antigen presenting cells for initiating
primary IR against protein antigens 2. Langerhans cells
̶ Immature dendritic cells within the epidermis. 3. Follicular dendritic cells
̶ Germinal centers of lymphoid follicles in spleen and LN
̶ Bears Fc receptors for IgG and C3b
̶ Trap antigen bound to antibody (Ab) or complement proteins Improving quality of humoral immune response Play a role in the pathogenesis of AIDS
Note:
Two major types according to Robbins namely interdigitating and follicular
10-15% of peripheral lymphocytes
Kill variety of tumor cells, virally infected cells, some normal cells without previous sensitization
Do not bear T-cell receptors, surface Ig nor the traditional T or B markers
Nucleus is not segmented
Morphologic name: Large granular lymphocytes Histological appearance: Huge lymphocytes
Has two receptors: Inhibitory receptor and activating receptor
Cancer patients take interferon for the possibility that NK cells will destroy the foreign bodies.
Cytokines IL-2, IL-15 and IL-12 regulate NK cells activity o IL-2 and IL-15 Proliferation of NK cells
o IL-12 Activates killing and secretion of IFN-γ
MLE Q: Killing dependent on cell to cell contact enhanced by interferon and IL-12
MLE Q: Antibody Dependent Cell mediated Cytotoxicity (ADCC):Ability to lyse IgG coated target cells due to CD16 cell surface molecules secrete cytokines such as IFN-γ
MLE Q: What receptor enhances NK cell killing? Answer: CD16Note:
CD16 is an Fc receptor of NK cells for IgG. It confers the ability on NK cells to lyse IgG-coated target cell. This reaction is called ADCC.
NK cells are early line of defense because of the ability to kill a variety of infected and tumor cells. It activates macrophages by secreting IFN-γ which provides an early defense against intracellular microbes.
Activation of B lymphocytes and elimination of extracellular microbes
B-cell lymphocyte mediated via production of antibody
MLE Q:Often develops as a response to soluble antigens B cells account for about 20% of circulating lymphocytes Immunoglobulin gene rearrangements allow tremendousdiversity of responses to many antigens.
Protects against extracellular microbes and toxins Can mutate/change in genetic coding to have different
responses
Fig 3. Immunoglobulin molecule. Note that there are two heavy (H) chains and
two light (L) chains linked by disulfide bonds. Each heavy and light chain has a constant (C) and a variable (V) region. It is the variable regions in the Fab portion that react with a specific antigen and give rise to the diversity of immunologic response. Immunoglobulin can attach via the Fc portion to a variety of cells with Fc receptors.
Steps in Humoral Immunity
1. Naive IgM and IgD B cell binds microbe 2. Helper T cells help B cells via:
a. CD40 on B cells recognize CD40L of T cells
b. IL-4 (secreted by TH2 helper cells) lead to matured B cells/ plasma cells IgE production
c. TH1 helper cells stimulated IgG Ab production 3. Class switching and affinity maturation occurs mainly in
germinal centers
4. Antibody secretion by plasma cells
̶ Ab’s bind to microbes “neutralizing” them, preventing them from infecting cells.
̶ IgG act as opsonins
Activation of T lymphocytes and elimination of intracellular microbes
Mediated by T lymphocytes T-cell receptors (TCR)
o Genetically programmed to recognize specific antigens o Can rearrange their alpha and beta genes to respond to
antigenic stimuli
Macrophages process the antigen and present it with class II Human Leukocyte Antigen (HLA) to the CD4+ cells
Cytokines such as interleukin (IL) and tumor necrosis factor (TNF) are elaborated by activated T cells to enhance cellular immune reactions
A. CD4+ helper lymphocytes
̶ Help B cells make antibody (therefore B cells are not exclusively for humoral immunity)
̶ Help generate cytotoxic T cells
̶ Macrophages process antigen and present it with class II HLA to the CD4+ cells
̶ Participate in delayed hypersensitivity reactions (TYPE IV) ̶ 60% of peripheral T lymphocytes
̶ Secrete and respond to growth factor IL-2 cytokine Proliferation and increase in number of CD4+ T cells
II. Cell-Mediated Immunity
I. Humoral Immunity
Two Broad Categories of the Immune System
Natural Killer Cells
SECTION B
UERMMMC Class 2014
Pathology 4 | 10
Table 1. Characteristics of the different CD4+ SubsetsCD4+ Subsets TH1 TH2 TH17 (Recently discovered) Cytokine secreted IFN-γ- potent macrophage activator IL-4 – Stimulate B cells to differentiate into IgE-secreting plasma cells IL-5 – Activates eosinophils IL-13 – Mucus secretion IL-17- play a role in several inflammatory diseases
Induced by IFN-γ and IL-12 IL-4 TGF-β, IL-1
etc Function Macrophage activation IgG production IgE production Mast cell and eosinophil activation Recruitment of neutrophils and monocytes Host defense against Intracellular microbes Helminthic parasites, allergens Extracellular bacteria and fungi Role in disease Immune-mediated chronic inflammatory diseases (often autoimmune) Allergies Immune-mediated chronic inflammatory diseases (often autoimmune) B. CD8+ suppressor lymphocytes
̶ Cytotoxic (mostly occur during cell-cell contact) ̶ 30% of circulating T lymphocytes
̶ Destroy infected and tumour cells
Physiologic function: To display peptide fragments of proteins for recognition by antigen-specific cells.
Play key roles in regulating T cell-mediated IR
MLE Q: MHC or human leukocyte antigen (HLA) complex is on chromosome 6Two Classes of MHCs
1. Class I Antigens: A, B and C
̶ Present on all nucleated cells and platelets (therefore is not seen in RBCs)
̶ Only class A and B are important in blood typing ̶ Encoded in loci/ regions HLA A, B and C ̶ Tested for and detected by serologic means ̶ "C" antigens unimportant
̶ A number of alleles are present and each person inherits one from each parent
̶ Thus, a person might be HLA typed as: a. A 5, 10
b. B 11, 41
2. Class II MHC Molecules: In the D region (DR) ̶ Narrowly distributed
̶ Mostly on mononuclear inflammatory cells (macrophages, B cells and dendritic cells) ̶ Help induce CD4+ cells
̶ Encoded in loci/region: HLA D (3 subregions: DP, DQ and DR)
̶ Recognized by CD4+ T lymphocytes ̶ Detected by mixed lymphocyte assay Importance of HLA
̶ Transplantation
̶ Regulation of some immune responses
Virus-infected cells with class I antigen are lysed by CD8+ cells that can recognize the virus-cell complex
MLE Q: Class II antigens help induce CD4+ cells ̶ Its association with a variety of diseases Inheriting HLA-B27 90% of developing ankylosing spondylitis and several postinfectiousarthropaties HLA-DR 2, -DR3 and –DR4 with autoimmune diseases
Notes:
HLA system is highly polymorphic – Meaning there are many alleles of each MHC gene in the population. Each individual inherits one set of these alleles, which is different from the alleles of other individuals. This is why there is a barrier in organ transplantation.
No 2 individuals (other than identical twins) are likely to
express the same MHC molecules and therefore grafts
exchange between these individuals are recognized as foreign and attacked by the immune system.
An individual inheriting a specific MHC molecule has its
own consequences/ advantages.
Ex. Inheriting MHC Class II specific for Ragweed pollen would be genetically prone to pollen allergies. In contrast, inheriting MHC Class II for bacterial antigens provide resistance to infection by evoking a protective antibody response.
Table 2. Mechanisms of Immunologically Mediated Diseases Type Prototype Disorder Immune Mechanisms Pathologic Lesions Immediate (type I) hypersensitivity Anaphylaxis; allergies; bronchial asthma (atopic forms) Production of IgE antibody Immediate release of vasoactive amines and other mediators
from mast cells Recruitment of inflammatory cells (late-phase reaction) Vascular dilation, edema, smooth muscle contraction, mucus production, inflammation Antibody-mediated (type II) hypersensitivity Autoimmune hemolytic anemia; Good pasture syndrome Production of IgG, IgM Binds to antigen on target cell
or tissue Phagocytosis or lysis of target cell by activated complement or Fc receptors; Recruitment of leukocytes Cell lysis; inflammation Immune complex-mediated (type III) hypersensitivity Systemic lupus erythematosus; some forms of glomerulonephrit is; serum sickness; Arthus reaction Deposition of antigen-antibody complexes Complement activation Recruitment of leukocytes by complement products and Fc receptors Release of enzymes and other toxic molecules Necrotizing vasculitis (fibrinoid necrosis); inflammation Cell-mediated (type IV) hypersensitivity Contact dermatitis; multiple sclerosis; type I, diabetes; transplant rejection; tuberculosis Activated T lymphocytes i. Release of cytokines and macrophage activation ii. T cell-mediated cytotoxicity Perivascular cellular infiltrates; edema; cell destruction; granuloma formation
Occurs within minutes after an antigen combines with an antibody (IgE) bound to mast cells in previously sensitized individuals
Anaphylaxis
o Occurs in individuals with prior sensitization o Promotes mast cell proliferation and IgE production of
plasma cells
o IgE and mast cells bind in places such as the respiratory tract mucosa
o Most threatening if person has it in the respiratory tract because patient can die due to asphyxia. It can cause vasodilation and bronchoconstriction which decreases effective blood circulation and may lead to shock Mast cells
̶ Found near blood vessels and nerves
̶ Almost same with Basophils, except that it does not roam around the circulation
̶ Contains granules:
1. Preformed and Stored in Cytoplasm (1⁰ mediators) a. Vasoactive amines – Histamine and serotonin
(vasodilation and bronchoconstriction) b. Enzymes – Cause tissue damage and kinin
production
c. Proteoglycans – Heparin
2. Lipid Mediators - de novo synthesis and release (2⁰ mediators) a. Leukotrienes b. Prostaglandin c. Platelet-activating factor d. Bradykinins Steps:
1. 1st exposure: Allergen binds to antibody
2. TH2 cells secrete IL-4 Stimulate IgE production 3. IgE’s Fc portion binds to mast cells
4. 2nd exposure: Allergen binds to IgE’s Fab portion (This
same IgE is the one bounded to a mast cell due to 1st exposure to allergen)
5. Bridging of Fc receptors Mast cell degranulation (Release of histamine and serotonin, leukotrienes, prostaglandin and bradykinin)
Fig 4. TYPE I hypersensitivity
Remember:
̶ 1st
exposure to antigen produces IgE but NO degranulation of mast cell
̶ 2nd
/re-exposure: Bridging of IgE to mast cell with antigen Degranulation
̶ Inflammatory cell infiltrates Immediate Reaction (In minutes)
̶ Vasodilation, vascular leakage, smooth muscle spasm and glandular secretions
Late Phase Reaction (2-24 hours)
̶ Leukocyte infiltration, epithelial damage, bronchospasms ̶ In late phase reaction, eosinophils are particularly important 1. Systemic
̶ Characterized by vascular shock, widespread edema and difficulty in breathing
̶ Cx: Itching, hives skin erythema, laryngeal edema, vomiting, abdominal cramps, diarrhea, laryngeal obstruction. Patient may go into shock and die in an hour
̶ Ex. Drug allergies (anaphylaxis), Food allergies (peanuts), Asthma, Insect toxins (bee sting), hay fever
Fig 5. Acute laryngeal edema due to anaphylactic reaction to penicillin. A form
of Type I hypersensitivity reaction where preformed IgE antibody on mast cells quickly reacts with antigen. Mast cells release histamine and other mediators leading to edema.
Types of Anaphylaxis
Type I (Immediate) Hypersensitivity
SECTION B
UERMMMC Class 2014
Pathology 6 | 10
2. Local (Atopy)
̶ Affects 10% of people
̶ Allergens include: Pollen, animal fur, dust, food etc. ̶ Easily sensitized to allergens that cause a localized
cutaneous swelling when inhaled or ingested ̶ Specific diseases include: Urticaria (hives),
angioedema, allergic rhinitis (hay fever), bronchial asthma, skin allergy, conjunctivitis and food allergies.
Fig 6. Hay Fever. A form of localized anaphylaxis with Type I hypersensitivity where
allergens in plant pollens contact IgE bound to mast cells then causing the release of granules containing mediators such as histamine that promote vasodilation and edema. Beneath the nasal mucosa at the left, eosinophils have been attracted. The plasma cells seen here have collected due to the chronic nature of the antigenic stimulation.
Caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix or altered cell surface antigens
Complement dependent reactions: Antibody directed against antigen on cells (circulating red blood cells) or extracellular materials (basement membrane).
Resulting Ag-Ab complexes activate complement (via the classic pathway) causing cell lysis and extracellular tissue damage.
Fig 7. In the above diagram, a red blood cell has antigen fixed on its surface to
which antibody attaches. The attached antibody sets off the complement cascade, which ends with the formation of the "membrane attack complex" of C5-9 which causes lysis of the cell. Other complement components may be generated, such as the opsonin C3b.
1. Phagocytosis and Opsonization ̶ Examples:
a. Transfusion reactions wherein incompatible red
blood cells (RBCs) or serum is transfused
b. Autoimmune hemolytic anemia in which antibodies
are made against one’s own RBCs
c. In erythroblastosis fetalis, there is an antigenic
difference between the mother and the fetus When maternal IgG crosses the placenta, it destroys fetal RBCs
2. Inflammation
̶ Ab’s are deposited to fixed tissues (basement membrane and extracellular matrix) Activate complement system Formation of the membrane attack complex which disrupts membrane integrity ̶ Examples:
Good Pasteur’s syndrome – Ab targets kidney
glomerular basement membrane/ GBM. Immunofloresces of GBM show a linear pattern because GBM becomes antigenic Linear deposition of cells.
3. Cellular Dysfunction/ Stimulation
̶ In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation.
̶ Examples:
a. Dysfunction: In myasthenia gravis, there are acetylcholine receptor antibodies in the motor end plates of skeletal muscles which block
neuromuscular transmission and diminish muscular response Muscle weakness. Ach has no receptor to bind to since the receptors are occupied by Ab thus no contraction occurs. Manifestations:
1st: Ptosis (bilateral) 2nd: Difficulty in breathing
b. Stimulation: In Graves disease, antibodies against the thyroid-stimulating hormone receptor antibodies on thyroid epithelial cells stimulate the cells, leading to hyperthyroidism
c. Dysfunction: In pernicious anemia, anti-parietal cell antibodies are present Decreased absorption of Vit. B12.
Antibody-mediated cell destruction may also occur via ADCC: o Low concentrations of IgG or IgE (in the case of parasites) Coat target cells Inflammatory cells such as NK (natural killer) cells, monocytes, and granulocytes bind to the immunoglobulin Fc receptors Lyse, but DO NOT phagocytize, the target cells
Fig 8. A macrophage with Fc receptors on its surface is able to recognize a target
cell coated with antibody via the Fc receptor portion of the attached antibody. The macrophage can then demolish the targeted cell by elaboration of proteases.
(Macrophage releasing proteases) tissue necrosis; inflammation Examples of ADCC
a. Transplant rejection
b. Immune reactions against neoplasms c. Immune reactions against parasites
Antireceptor antibodies: IgG antibody is directed against receptors in target cells, resulting in complement-mediated destruction of the receptors.
Antibody-Dependent Cell-mediated Cytotoxicity
(ADCC)
Mechanisms of Type II Hypersensitivity
Fig 9. In the diagram, antibody is directed against acetylcholine receptors at the
motor end plate of a muscle, blocking the receptors and diminishing the muscular response. This is the mechanism for muscle weakness in myasthenia gravis.
Diseases caused by this mechanism include: ̶ Myasthenia gravis: Ach receptor antibody.
̶ Grave's disease (thyrotoxicosis): Anti-TSH receptor antibody ̶ Pernicious anemia: Anti-parietal cell antibody.
Mediated by immune (Ag-Ab) complexes (IC) which promote tissue damage primarily through complement activation (alternate pathway)
o C3b, as an opsonin, attracts neutrophils, which then release lysosomal enzymes.
o C5a as a chemoattractant brings in neutrophils. o Serum complement is reduced as it is used up in this
process.
Fig. 10. Antibody-Antigen complex promotion
Antigen-antibody complexes are circulating and becoming trapped beneath the basement membrane of a small blood vessel, setting off the complement cascade and generating components that attract PMN's to generate an ongoing inflammatory response (Figure above).
In this type of hypersensitivity reaction, there is a mark element of VASCULITIS.
Immune complexes can be deposited systemically or locally (deposited near Basement membranes)
Pathogenesis of Systemic Immune Complex Disease 1. Ag-Ab complexes form in the circulatory system
̶ Protein/ Ag is introduced leading to formation of Ab’s in blood
2. Deposition of Immune Complexes in various tissues ̶ Larger immune complexes are quickly phagocytized
by macrophages and removed. The larger they are, they are more easily recognized and phagocytized. ̶ The smaller to intermediate complexes formed
within antigen excess may escape removal. They are the most pathogenic and are not recognized hence they are opsonized. These complexes are deposited to organs w/c filter at high pressure. (Glomeruli, Joints and BV)
̶ This may lead to: Glomerulonephritis Serum sickness Vasculitis
3. Initiating Inflammation caused by deposition of IC ̶ Because small IC’s are opsonised, they trigger
complement system
̶ The resultant inflammatory lesions are the ff: Glomerulonephritis – Red/white cell becomes
immunogenic to own system, circulate and deposited in glomerular capillaries
Vasculitis – Deposited in and around small blood vessel inciting an inflammatory reaction
Arthritis – In joints
Note:
A single large exposure to antigen/ Ag excess in circulation leads to Acute Serum Sickness.
Repeated or prolonged exposure Chronic form of Serum Sickness ex. Systemic Lupus Erythematosus (SLE).
Local immune complex disease: "Arthus" reaction
o Arthus reaction – Localized area of tissue necrosis from acute IC vasculitis.
o Local injection of the antigen Immune complex
formation Acute inflammatory hemorrhagic reaction and local dermal vasculitis.
o Role in the development of hypersensitivity pneumonitis ("farmer's lung") –Small complexes are deposited in the basement membrane of alveolar wall
No anti-body formation
Sensitization of T-lymphocyte CD4 containing leukocytes The lymphocyte with then secrete cytokines to act on the
macrophage
“Delayed” – Mediated by sensitized CD4+ T lymphocytes, which process antigens in association with class II HLA molecules and release lymphokines
The lymphokines promote a reaction (especially mediated through macrophages) beginning in hours but reaching a peak in 2 to 3 days.
Hypersensitivity reactions with this mode of action include: o Granulomatous diseases (Mycobacteria – Tuberculosis ,
fungi)
Fig 11. Sequence of events in granuloma formation in response to Mycobacterium
tuberculosis (MTB). The key cell in the process is the epithelioid macrophage.
CD4+ Lymphocyte-Mediated Responses
Local Immune Complex Disease
Systemic Immune Complex Disease
Type IV (Delayed) Hypersensitivity
Type III (Immune Complex-Mediated)
SECTION B
UERMMMC Class 2014
Pathology 8 | 10
MLE Q: What produces caseation in TB?Answer: It’s the Immune Response, NOT the organism
MLE Q: What is the hallmark of granuloma formation?Answer: Activation of macrophage
Epitheloid cell formationo Tuberculin skin reactions – Produced by intracutaneous injection of protein tuberculin from Bacillus in previously sensitized patient Accumulation of CD4+ T cells and macrophages around venules (perivascular “cuffing”)
MLE Q: Would HIV in chronic stage have caseousnecrosis?
Answer: NO, because no epitheloid formation that could destroy the organism.
o Transplant rejection
o Contact dermatitis – Pre-sensitized lymphocytes led to this inflammatory reaction a couple of days after contact with the offending agent (poison oak, poison ivy) CD8+ T cells generated Lyse specific cells
Role of Class I HLA molecules: CTL bind MHC I Ag of cells, kill them, enacting cell mediated immune response
Reactions with this mode: o Neoplastic cell lysis o Transplant rejection o Virus-infected cell lysis o Viral Hepatitis
Note:
Difference of Type 4 vs. Type 3
Greater phagocytosis, no deposition in basement membrane, no Ig participation
Rejection of graft or donor organ
Graft versus Host (GVH) disease – Graft accepted but is manifesting symptoms, host reacting to transplanted organ
A. HLA system is a key factor.
̶ Reactions mediated by either T lymphocytes (cellular) or Ab (humoral)
̶ Major types of hypersensitivity reactions involved: II & IV B. The ABO system:
̶ Best characterized as the major blood group antigens ̶ Expressed on all cells except in the CNS
̶ Thus, matching for ABO compatibility is important for transplantation.
C. T-cell mediated reactions:
̶ CD4+ cells generating delayed hypersensitivity reactions after recognizing foreign HLA class II (DR) antigens (seen in mononuclear cells)
̶ Cytotoxic CD8+ cells recognizing foreign HLA class I (A,B, or C) antigens (in all nucleated cells). The donor tissue or donor lymphocytes within the transplanted tissue carry the offending HLA antigens. Involves suppressor reactions.
Note:
According to Robbins, T-cell mediated rejection has 2 pathways, Indirect and Direct. Direct pathways involve both CD4+ and CD8+ recognizing the donor’s APC’s. Indirect pathways involve only CD4+ (type IV hypersensitivity) responding to recipient’s own APC’s presenting donor’s antigen.
D. Antibody mediated reactions: ̶ Mediated through:
Complement-mediated cytotoxicity Antibody-dependent cytotoxicity (ADCC) Immune complexes
Can also be termed rejection vasculitis, because the 1st target of the antibodies seems to be the graft vasculature
Note:
According to Dr. Cu, there is no granuloma in HIV because HIV kills CD4+ responsible for granuloma formation.
3 Classic modes of rejection 1. Hyper-acute rejection:
̶ Occurs within minutes or hours after transplantation ̶ Kidney becomes cyanotic, mottled, flaccid and may
excrete blood in urine (needed: erythropoietin tests) ̶ Ig and complement deposited in vessel wall Thrombi,
endothelial injury and accumulation of neutrophils the site May lead to kidney infarction
̶ Preformed antibody causes immediate (minutes to hours) vascular injury via ADCC
̶ Due to previous sensitization through transfusion, pregnancy, or infections (through HLA cross-reacting bacterial or viral antigens)
2. Acute rejection – Both cell mediated and humoral immunity involvement
̶ Acute Cellular rejection:
Occurrence sometimes within days, usually within months, even sometimes years later when immunosuppressive therapy is discontinued. Cellular infiltrates with both CD4+ and CD8+ cells. Primarily T cell mediated cytotoxic damage There is tubular damage and vascular injury due to
CD8+
Density of the infiltrate and extent of parenchymal
damage determine severity (more inflammatory
reaction, more tissue destruction due to dissolution of immune complex)
̶ Acute Vascular (or Humoral) Rejection (rejection
vasculitis)
Rejection primarily at the vasculature of the graft because of anti-donor antibodies
3 general stages:
1. Early: Subendothelial inflammation and hypertrophy of endothelium
2. Intermediate: moderate intimal proliferation with more significant wall inflammation 3. Severe: Significant fibrinoid necrosis
(indicator of immune damage) and intimal proliferation.
CD8+ Lymphocyte (CTL)-Mediated Responses
Renal Transplant
Organ System Pathology
Immunologic Mechanisms
Two Important Pathologies in Transplant Rejection
TRANSPLANT REJECTIONS
Fig 12. This is an Acute renal transplant rejection known as acute cellular
tubulointerstitial rejection because most of the inflammation is in the interstitium. The glomerulus seen here is normal, but the tubules are infiltrated by many lymphocytes at the upper right (coagulative necrosis). Organ is still discernible.
Fig 13. At high magnification, the lymphocytes and plasma cells are seen around a
renal tubule in a renal transplant patient with acute cellular rejection. This type of rejection can occur at any time following transplantation when immunosuppression is diminished. This is treated by administering cyclosporine and other immunosuppressive agents.
3. Chronic rejection (Chronic transplant Glomerulopathy) ̶ More tissue fibrosis/ scar formation
̶ Scar formation Vessel obliteration
̶ Chronic rejection Renal failure Increase serum creatinine
̶ Tubular atrophy and shrinkage of renal parenchyma ̶ Intimal fibrosis with vascular thickening Renal
ischemia
̶ Mononuclear infiltrates with prominent plasma cells and eosinophils
̶ Both T-cell and humoral mechanisms leads to
increasing intimal fibrosis and ischemia
̶ Obliterates vessels, almost no blood supply to surrounding structures
̶ Hallmark of chronic rejection is increased fibrosis
Fig 14. Immunologic disease can also complicate solid organ transplantation. Here
is a renal biopsy that demonstrates marked interstitial fibrosis in a patient with chronic vascular rejection.
Fig 15. Chronic vascular rejection at high magnification: thickened and fibrotic renal
arteries; obliterated lumen. There is interstitial fibrosis and chronic inflammation. Such chronic rejection usually occurs slowly over several months to years following transplantation. This form of rejection, unlike acute cellular rejection, is difficult to treat.
Graft vs. Host Disease
̶ An immune reaction of the host against a graft (e.g. organ) ̶ 2 phases
1. Acute: Cell necrosis of skin and GI tract, cholestasis 2. Chronic: Over 100 days post transplant
Dermal fibrosis, desquamative esophagitis, portal tract fibrosis Cholestasis
̶ 3 organs prominently involved: a. Liver (cholestasis) b. Intestine
c. Skin (apoptosis of squamous epithelium and thickening of subepidermal region with increased hyalinization) ̶ In BM transplant, GvH is the greatest problem, however, in
case of bone marrow malignancy transplant, graft vs. tumor effect is therapeutic
̶ Recall difference of necrosis and apoptosis( Board exam question)
Fig 16. Liver cholestasis. Seen above are large collections of yellow-green bile
pigment within the bile canaliculli
Fig 17. Thickness of subepithelial region; hyalinization of skin. Besides the
icterus (yellow color, or jaundice) in this skin there is a fine scaling rash in this patient following bone marrow transplantation with a 5 out of 6 antigen match. This is an example of graft versus host disease (GVHD) where donor lymphocytes attack host tissues.
SECTION B
UERMMMC Class 2014
Pathology 10 | 10
Fig 18. Apoptosis or single cell necrosis – there is vacuolization and dissolution ofepidermal cells along the basal layer, along with lymphocytes. At the arrow is a rounded pink apoptotic body.
HLA is less important than simple matching of organ size (since most of these are done in children).
Two modes of rejection: a. Acute rejection
̶ Seen within two months
̶ Mixed inflammatory portal and central vein infiltrates.
b. Chronic rejection
̶ Continued inflammation, portal fibrosis, arteriolar thickening, and bile ductular necrosis
Note:
In heart liver and lungs, HLA matching is usually not even done, because anatomic compatibility (ex. Size), severity of underlying illness and minimizing the time of organ storage have much more benefits over HLA matching.
HLA is less important than simple matching of organ size. Immunosuppressive therapy is carefully monitored in
relationship to signs of rejection on endomyocardial biopsy. Two modes of rejection:
o Acute cellular rejection:
Lymphocytic infiltrates
Possible myocardial fiber necrosis. o Acute vascular rejection:
Immunoglobulin deposition in small arteries Vasculitis.
Fig 19. This is acute vascular rejection in a myocardial transplant tissue. The
inflammatory reaction consists mostly of mononuclear infiltration (lymphocytes) and is seen mainly around small arteries, a vasculitis. Such a reaction can occur when the dose of immunosuppressive drugs is decreased in the months following transplantation. Increasing immunosuppressive therapy in these patients is not as effective as for acute cellular rejection.
Fig 20. By immunoperoxidase staining with antibody to CD3, the T-lymphocytes in
the myocardium involved in this acute cellular rejection phenomenon in a heart transplant recipient can be identified here.
Two problems that are unique to bone marrow transplant are Graft versus host disease and immunodeficiency.
HLA matching important to minimize GvHD.
(GVHD) Donor lymphocytes attack recipient tissues having the offending HLA antigens.
Chemotherapy agents used to prepare patient for marrow transplantation may result in hepatic veno-occlusive disease in the weeks following transplantation.
Robbin’s Pathologic Basis of Disease: Disease of Immunity
2013B Trans: Immunopathology Dr. Cu’s Lecture
1. One of the two important cellular reactions of innate immunity as anti-viral defense together with NK cells 2. This is necessary for B-cell maturation and secretion of IgA,
IgG, and IgE
3. Most important antigen presenting cells 4. MHC Class II can be detected by _______ 5. In type I hypersensitivity, this causes mast cell
degranulation.
6. What mechanism causes autoimmune hemolytic anemia in type II Hypersensitivity
7. TRUE/FALSE: In type III Hypersensitivity, deposition should takes place first before formation of immune complexes. 8. Would HIV in chronic stage cause caseous necrosis? 9. What type of classic mode of rejection is where
fibrosis/scarring are predominantly seen?
10. The 3 organs predominantly involved in GVHD are skin, liver and ____.