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Pathology of the immune response. Hypersensitivity reactions. Autoimmune diseases.
Pathology of the immune response. Immunologic deficiency syndromes. Transplantation immunity
Questions
Immunity. Types. Morphological basis.
Pathological immune reactions. Autoimmune diseases.
Immunologic deficiency syndromes – primary and secondary.
Transplantation immunity. Reaction of transplant rejection.
Immunity
INNATE (present before birth, “NATURAL”)
ADAPTIVE (developed by exposure to pathogens, or in a broader sense, antigens)
Innate (natural, nonspecific) immunity
Antigen-independent cells providing first defense against pathogens
Types of cells Phagocytic cells (e.g., neutrophils,
macrophages) Natural killer cells
INNATE IMMUNITY
Barriers Cells
lymphocytes, macrophages, plasma cells, NK cells
Cytokines/chemokines Plasma proteins
Complement, Coagulation Factors Toll-like receptors (TLR’s)
Acquired (specific) immunity
Antigen-dependent activation and expansion of lymphocytes
cellular T cells are involved in cell-mediated immune
responses to antigens humoral
B lymphocytes produce antibodies
Cells of the Immune System
LYMPHOCYTES, T LYMPHOCYTES, B PLASMA CELLS (modified B cells) MACROPHAGES (“HISTIOCYTES”)
Antigen Presenting Cells (APCs) “DENDRITIC” CELLS
Antigen Presenting Cells (APCs) NK (NATURAL KILLER) CELLS
Cells of the Immune SystemCell Type Derivation Location Function
T cells CD4 (helper) CD8 (cytotoxic/suppressor)
Bone marrow lymphocytestem cells mature inthymus
Peripheral blood and bonemarrow, thymus, paracortex of lymph nodes, Peyer's patches
CD4 cells: secrete cytokines (IL-2 → proliferation of CD4/CD8 T cells; γ-interferon → activation of macrophages); help B cells become antibody-producing plasma cellsCD8 cells: kill virus-infected, neoplastic, and donor graft cells
B cells Bone marrow stem cells
Peripheral blood and bone marrow, germinal follicles in lymph nodes, Peyer's patches
Differentiate into plasma cells that produce immunoglobulins to kill encapsulated bacteria (e.g., Streptococcus pneumoniae)Act as APCs that interact with CD4 cells
Natural killercells
Bone marrow stemcells
Peripheral blood (large granular lymphocytes)
Kill virus-infected and neoplastic cells
Macrophages Conversion of monocytes into macrophages in connective tissue
Connective tissue; organs(e.g., alveolar macrophages, lymph node sinuses)
Involved in phagocytosis and cytokine Production Act as APCs
Dendritic cells Bone marrow stemcells
Skin (Langerhans' cells), germinal follicles
Act as APCs
L
Y
M
P
H
S
1) ROUND NUCLEUS
2) OVOID CYTOPLASM
3) PERIPHERAL CHROMATIN
4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF CYTOPLASM
PLASMA CELLS
Lymph nodes and spleen-lymphocytes B and T location
MACROPHAGES are MONOCYTES that have come out of circulation and have gone into tissue
Dendridic cells
A type of macrophage with many spiny cytoplasmic processes, found in many places skin (Langhans cells) brain (microglia)
They are also APC’s.
Natural killer cells (NK cells)
A type of cytotoxic lymphocyte
a major component of the innate immune system
NK cells play a major role in the rejection of tumors and cells infected by viruses.
The cells kill by releasing small cytoplasmic granules of proteins (perforin and granzyme)
that cause the target cell to die by apoptosis.
General scheme of cellular events
APCs (Macrophages, Dendritic Cells) T-Cells (Control Everything)
CD4 “REGULATORS” (Helper) CD8 “EFFECTORS”
B-Cells Plasma Cells AB’s NK Cells
CYTOKINES
Proteins produced by many cells -Ly and macrophages
Numerous roles in acute and chronic inflammation, and immunity mediate innate (natural) immunity
IL-1, TNF, Interferons regulate lymphocyte growth
many interleukins, ILs activate inflammatory cells stimulate hematopoesis,
Colony Stimulating Factors, CSFs CHEMOKINES (small proteins) -attractants for PMNs
MHCMajor Histocompatibility Complex
A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility
Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice
It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated
Major Histocompatibility Complex (MHC)
Location Short arm of chromosome 6
Human leukocyte antigen (HLA) genes
Code for HLA proteins that are unique to each individual
HLA association with disease HLA-B27 with ankylosing
spondylitis HLA-DR2 with multiple
sclerosis HLA-DR3 and -DR4 with type 1
diabetes mellitus
Class I MHC molecules Coded by HLA-A, -B, and -C
genes Present on the membranes
of all nucleated cells Not present on mature
RBCs; present on platelets Recognized by CD8 T cells
and natural killer cells Class II MHC molecules Coded by HLA-DP, -DQ, and
-DR genes Present on antigen-
presenting cells (APCs) B cells, macrophages,
dendritic cells Recognized by CD4 T cells
MHC MOLECULES (Gene Products)
I (All nucleated cells and platelets), cell surface glycoproteins, ANTIGENS
II (APC’s, i.e., macs and dendritics, lymphs), cell surface glycoproteins, ANTIGENS
III Complement System Proteins
IMMUNE SYSTEM DISORDERS
HYPERSENSITIVITY REACTIONS I-IV types
“AUTO”-IMMUNE DISEASES “collagen” diseases
IMMUNE DEFICIENCY SYNDROMES: primary (genetic) secondary (acquired)
Hypersensitivity Reactions
Pathologic or excessive reactions against an antigen are manifestations of "hypersensitivity
May result from various underlying abnormalities Autoimmunity Reactions against microbes
Str., tbc
Reactions against environmental antigens pollens, animal danders, or dust mites
Chronic inflammation, is the major component of the pathology of these disorders
immune-mediated inflammatory diseases
Hypersensitivity Reactions
I (Immediate Hypersensitivity) II (Antibody Mediated
Hypersensitivity) III (Immune-Complex Mediated
Hypersensitivity) IV (Cell-Mediated Hypersensitivity)
Hypersensitivity Reactions Reaction Pathogenesis Examples
Type I IgE-dependent activation of mast cells
Atopic disorders: hay fever, eczema, hives, asthma, reaction to bee stingDrug hypersensitivity: penicillin rash or anaphylaxis
Type II
Antibody-dependent reaction
Complement-dependent reactions
Lysis: ABO mismatch, Goodpasture's syndrome, hyperacute transplantation rejection
Phagocytosis: warm (IgG) autoimmune hemolytic anemia, ABO and Rh hemolytic disease of newborn
Complement-independent reactions
Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity: natural killer cell destruction of neoplastic and virus-infected cells; helminth destruction by eosinophils
Antibodies directed against cell surface receptors: myasthenia gravis, Graves' disease
Type III Deposition of antigen-antibody complexes
Systemic lupus erythematosus (DNA-anti-DNA)Rheumatoid arthritis (IgM-Fc receptor IgG)Serum sickness (horse antithymocyte globulin-antibody)
Type IV Antibody-independent T cell-mediated reactions
Delayed type: contact dermatitis (e.g., poison ivy), tuberculous granulomaCell-mediated cytotoxicity: killing of tumor cells and virus-infected cells
Type I (immediate) hypersensitivity
Also called allergic reactions, or allergies
Induced by environmental antigens (allergens) that stimulate strong TH2 responses and IgE production in genetically susceptible individuals
IgE coats mast cells by binding to Fcε receptors
re-exposure to the allergen leads to cross-linking of the IgE and FcεRI, activation of mast cells, and release of mediators.
Mediators are responsible for the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation).
Principal mediators are histamine, proteases and other granule contents prostaglandins and leukotrienes cytokines.
The clinical manifestations may be local - rhinitis systemic -anaphylaxis.
Type I (immediate) hypersensitivity
Allergen exposure IMMEDIATE phase: MAST cell
DEgranulation, vasodilatation, vascular leakage, smooth muscle spasm
LATE phase (hours, days): Eosinophils, PMNs, T-Cells
Clinical examples of type I hypersensitivity
Anaphylaxis, allergies, bronchial asthma (atopic forms)
Tests used to evaluate type I hypersensitivity
Scratch test Positive response is a histamine-mediated
wheal-and-flare reaction after introduction of an allergen into the skin.
Radioimmunosorbent test Detects specific IgE antibodies in serum that
are against specific allergens
Type II (cytotoxic) hypersensitivity
Antibody-dependent cytotoxic reactions Complement-dependent reactions
Lysis Antibody (IgG or IgM) directed against antigen on the cell membrane
activates the complement system, leading to lysis by the membrane attack complex.
Phagocytosis Fixed macrophages (e.g., in spleen) phagocytose hematopoietic cells
(e.g., RBCs) coated by IgG antibodies and/or complement (C3b). Complement-independent reactions
Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity Leukocytes with receptors for IgG or IgE lyse but do not phagocytose
cells coated by antibodies. IgG autoantibodies directed against cell surface receptors
Tests used to evaluate type II hypersensitivity Direct Coombs' test detects IgG and/or C3b attached to RBCs. Indirect Coombs' test detects antibodies in serum (e.g., anti-D).
Type II (cytotoxic) hypersensitivity
Effector mechanisms A, Opsonization of cells by
antibodies and complement components, and ingestion of opsonized cells by phagocytes.
B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products.
C, Antireceptor antibodies disturb the normal function of receptors.
antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease
acetylcholine (ACh) receptor antibodies impair neuromuscular transmission in myasthenia gravis.
Antibody-Mediated Diseases (Type II Hypersensitivity)
Autoimmune Hemolytic Anemia, AHA Idiopathic Thrombocytopenic Purpura, ITP Goodpasture Syndrome
Nephritis and Lung hemorrhage Rheumatic Fever Myasthenia Gravis Graves Disease Pernicious Anemia, PA
Type III (immunocomplex) hypersensitivity
Activation of the complement system by circulating antigen-antibody complexes
First exposure to antigen Synthesis of antibodies
Second exposure to antigen Deposition of antigen-antibody complexes Complement activation, producing C5a, which attracts
neutrophils that damage tissue Arthus reaction
Localized immunocomplex reaction Example-farmer's lung from exposure to thermophilic
actinomycetes, or antigens, in air Test used to evaluate type III hypersensitivity
Immunofluorescent staining of tissue biopsies example-glomeruli in glomerulonephritis
Type III (immunocomplex) hypersensitivity
Antigen/Antibody “Complexes” Kidney (Glomerular Basement
Membrane) Blood Vessels Skin Joints
Common Type III Diseases SLE (Lupus), Poly(Peri)arteritis Nodosa, Poststreptococcal
Glomerulonephritis, Arthus reaction (hrs), Serum sickness (days)
Type IV hypersensitivity Antibody-independent T cell-mediated reactions
(cellular immunity) Delayed reaction hypersensitivity
CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine injury to tissue.
Cell-mediated cytotoxicity CD8 T cells interact with altered MHC class I antigens on
neoplastic, virus-infected, or donor graft cells, causing cell lysis.
Test used to evaluate type IV hypersensitivity Patch test to confirm contact dermatitis
Example-suspected allergen (e.g., nickel) placed on an adhesive patch is applied to the skin to see if a skin reaction occurs.
Skin reaction to Candida Clinical examples of type IV hypersensitivity
Type IV hypersensitivity
Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions.
A, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury.
B, In some diseases, CD8+ CTLs directly kill tissue cells.
Type IV hypersensitivity
Tuberculin Skin Reaction
DIRECT ANTIGENCELL CONTACT GRANULOMA FORMATION CONTACT DERMATITIS
SUMMARY
I Acute allergic reaction
II Antibodies directed against cell surfaces
III Immune complexes
IV Delayed Hypersensitivity (Tb skin test)
Autoimmune Diseases Autoimmune dysfunction is associated with a loss of self-
tolerance, resulting in immune reactions directed against host tissue.
Tolerance (unresponsiveness) to self-antigens is a fundamental property of the immune system
Central tolerance: immature lymphocytes that recognize self-antigens in the central
(generative) lymphoid organs are killed by apoptosis; I n the B-cell lineage, some of the self-reactive lymphocytes switch to new
antigen receptors that are not self-reactive. Peripheral tolerance
mature lymphocytes that recognize self-antigens in peripheral tissues become functionally inactive (anergic), or are suppressed by regulatory T lymphocytes, or die by apoptosis.
The variables that lead to a failure of self-tolerance and the development of autoimmunity include
inheritance of susceptibility genes that may disrupt different tolerance pathways,
infections and tissue alterations that may expose self-antigens and activate APCs and lymphocytes in the tissues.
Mechanisms of autoimmunity
Release of normally sequestered antigens (e.g., sperm)
Sharing of antigens between host and pathogen
Defects in functions of helper or suppressor T cells
Persistence of autoreactive T and B cells
Presence of specific autoantibodies
CLASSIC AUTOIMMUNE DISEASESSYSTEMIC
Systemic lupus erythematosus Rheumatoid arthritis Sjögren syndrome Systemic sclerosis (scleroderma)
Mixed connective tissue disease
CLASSIC AUTOIMMUNE DISEASES LOCAL
Hashimoto thyroiditis Autoimmune hemolytic anemia Multiple sclerosis Autoimmune orchitis Goodpasture syndrome Autoimmune thrombocytopenia “Pernicious” anemia Insulin dependent diabetes mellitus Myasthenia gravis Graves disease
Autoantibodies in Autoimmune Disease
Autoantibodies DiseaseTest Sensitivity
(%)
Antiacetylcholine receptor Myasthenia gravis 90
Anti-basement membrane Goodpasture syndrome >90
Anticentromere CREST syndrome 30
Antiendomysial and antigliadin Celiac disease 95
Anti-insulin, Anti-islet cell Type 1 diabetes 50, 75
Anti-intrinsic factor Pernicious anemia 60
Anti-parietal cell 90
Antimicrosomal Hashimoto's thyroiditis 97
Antithyroglobulin 85
Antimitochondrial Primary biliary cirrhosis 90-100
Antimyeloperoxidase Microscopic polyangiitis 80 (p-ANCA)
Antiproteinase 3 Wegener's granulomatosis >90 (c-ANCA)
Antiribonucleoprotein Mixed connective tissue disease 100
Anti-TSH receptor Graves' disease 85
Systemic lupus erythematosus (SLE)
A systemic autoimmune disease caused by autoantibodies produced against numerous self-antigens and the formation of immune complexes.
Anti-nuclear autoantibodies, and the ones responsible for the formation of circulating immune complexes, are directed against nuclear antigens.
Other autoantibodies react with erythrocytes, platelets, and various complexes of phospholipids with proteins.
The underlying cause of the breakdown in self-tolerance in SLE is unknown
Systemic lupus erythematosus (SLE)
Clinical findings Hematologic - autoimmune hemolytic anemia, thrombocytopenia,
leukopenia Lymphatic - generalized painful lymphadenopathy, splenomegaly Musculoskeletal - small-joint inflammation (hands) with absence of
joint deformity Skin - malar butterfly rash Renal – 5 types, diffuse proliferative glomerulonephritis the most
often Cardiovascular - fibrinous pericarditis with or without effusion,
Libman-Sacks endocarditis (sterile vegetations on mitral valve) Respiratory interstitial fibrosis of lungs, pleural effusion with
friction rub Pregnancy-related
complete heart block in newborns Recurrent spontaneous abortions
Drug-induced lupus erythematosus Associated drugs - Procainamide, hydralazine
Systemic lupus erythematosus (SLE)
Etiology: Antibodies (ABs) directed against the patient’s own DNA, HISTONES, NON-histone RNA, and NUCLEOLUS
Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS
Morphology: “Butterfly” rash, skin deposits, glomerolunephritis (NOT discoid)
Clinical expression: Progressive renal and vascular disease, POSITIVE A.N.A.
SLE, SKIN SLE, GLOMERULUS
Systemic lupus erythematosus (SLE)
Laboratory findings in SLE Antinuclear antibody (ANA) (almost all cases)
Anti-double-stranded DNA antibodies and anti-Sm antibodies Used to confirm the diagnosis of SLE -highly specific for the
disease Antiphospholipid antibodies
Lupus anticoagulant and anticardiolipin antibodies Damage vessel endothelium, producing vessel thrombosis Increased incidence of strokes and recurrent spontaneous
abortions Lupus erythematosus cell
Neutrophil containing phagocytosed altered DNA Not specific for SLE
Decreased serum complement Used up with activation of complement system
Immunocomplexes at the dermal-epidermal junction in skin biopsies
Immunofluorescent studies identify complexes in a band-like distribution along the dermal-epidermal junction.
Rheumatoid Arthritis Asystemic, chronic inflammatory disease
affecting many tissues but principally attacking the joints
to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis
In extra-articular involvement (skin, heart, blood vessels, muscles, and lungs)-RA may resemble SLE or scleroderma
Immunology genetic predisposition, infections T-cell reaction, TNF –central role Rheumatoid factor (RF or RhF) -
antibody against the Fc portion of Ig G immune complexes
Rheumatoid Arthritis Symmetric arthritis, principally
affecting the small joints of the hands (proximal interphalangeal and metacarpophalangeal joints) and feet, ankles, knees, wrists, elbows, and shoulders.
Morphology Pannus formation, destruction of
bone, cartilage, ankylosis synovial cell hyperplasia and
proliferation; dense perivascular inflammatory
cell infiltrates (frequently forming lymphoid follicles) in the synovium composed of CD4+ T cells, plasma cells, and macrophages
increased vascularity due to angiogenesis
neutrophils and aggregates of organizing fibrin on the synovial surface and in the joint space
increased osteoclast activity in the underlying bone, leading to synovial penetration and bone erosion
A pannus, formed by proliferating synovial-lining cells admixed with inflammatory cells, granulation tissue, and fibrous connective tissue
Rheumatoid Arthritis Morphology
Rheumatoid subcutaneous nodules - in about one-fourth of patients, occurring along the extensor surface of the forearm or other areas subjected to mechanical pressure
rarely they can form in the lungs, spleen, heart, aorta, and other viscera.
firm, nontender, oval or rounded masses as large as 2 cm in diameter.
Microscopically, they are characterized by a central focus of fibrinoid necrosis surrounded by a palisade of macrophages, which in turn is rimmed by granulation tissue
Pleuritis/pericarditis -fibrinous Lung - interstitial fibrosis. Ocular changes –uveitis,
keratoconjunctivitis
Systemic Sclerosis (Scleroderma)
Excessive production of collagen that primarily targets the skin, GIT, lungs, and kidneys
Occurs predominantly in women of childbearing age
Pathogenesis Small-vessel endothelial cell
damage produces blood vessel fibrosis and ischemic injury.
T-cell release of cytokines results in excessive collagen synthesis.
clawlike appearance , ulcerations
increase of compact collagen in the dermis along with thinning of the epidermis, atrophy of the dermal appendages, and hyaline thickening of the walls of dermal arterioles and capillaries
Systemic Sclerosis (Scleroderma)
Two groups based on its clinical course Diffuse scleroderma, characterized by initial widespread
skin involvement, with rapid progression and early visceral involvement
Limited scleroderma (CREST syndrome) - with relatively mild skin involvement, often confined to the fingers and face and involvement of the viscera occurs late
C-calcification, centromere antibody R-Raynaud's phenomenon E-Esophageal dysmotility S-sclerodactyly (i.e., tapered, claw-like fingers) T-telangiectasis (i.e., multiple punctate blood vessel dilations)
Laboratory findings in systemic sclerosis Serum ANA is positive in 70% to 90% of cases.
Antitopoisomerase antibody –in diffuse sclerosis Anticentromere antibodies in 30% of cases
Systemic Sclerosis (Scleroderma)
Clinical findings/Morphology Raynaud's phenomenon
Sequential color changes caused by digital vessel vasculitis and fibrosis, digital infarcts
heart (cardiac Raynaud) - microvascular injury and resultant ischemia Skin
Skin atrophy and tissue swelling beginning in the fingers and extending proximally
Extensive dystrophic calcification in subcutaneous tissue Tightened facial features (radial furrowing around the lips)
Gastrointestinal Dysphagia for solids and liquids Malabsorption Diverticula (bacterial overgrowth) Progressive atrophy and collagenous fibrous replacement of the
muscularis at any level of the gut Respiratory
Interstitial fibrosis of lungs, respiratory failure Renal
Vasculitis involving interlobular arteries and glomeruli, hypertension
Dermatomyositis /polymyositis
Immune-mediated muscle injury and inflammation
Occurs predominantly in women 40 to 60 years of age
Associated with risk of malignant neoplasms (15-20% of cases), particularly lung cancer, stomach
Pathogenesis DM is associated with antibody-mediated damage. PM is associated with T cell-mediated damage.
Clinical findings Muscle pain and atrophy
large muscles of the trunk, neck, and limbs Shoulders are commonly involved.
Heliotrope eyelids or "raccoon eyes" (purple-red eyelid discoloration)
Laboratory findings Serum ANA is positive in fewer than 30% of cases
Jo-1 antibodies, directed against transfer RNA synthetase .
Increased serum creatine kinase Muscle biopsy shows a lymphocytic infiltrate.
Polyarteritis Nodosa A systemic vasculitis of small or medium-sized
muscular arteries, typically involving renal and visceral vessels but sparing the pulmonary circulation
segmental transmural necrotizing inflammation (part of the vessel circumference)
acute phase there is transmural inflammation of the arterial wall with a mixed infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis
The inflammatory process weakens the arterial wall and can lead to aneurysms or even rupture
The most common manifestations are: malaise, fever, and weight loss hypertension, usually developing rapidly abdominal pain and melena (bloody stool) caused by
vascular GI lesions diffuse muscular aches and pains peripheral neuritis, predominantly affecting motor
nerves Renal (arterial) involvement –a common and a major
cause of death Biopsy is necessary to confirm the diagnosis
30% of patients - HBsAg-HBsAb immune complexes .
Mixed connective tissue disease (MCTD)
Signs and symptoms similar to SLE, systemic sclerosis, and PM distinct disease or represents
heterogeneous subsets of SLE, systemic sclerosis, and PM
Renal disease is uncommon. Immunology
Antiribonucleoprotein antibodies are positive in almost 100% of cases.
Sjögren Syndrome An inflammatory disease that affects
primarily the salivary and lacrimal glands, causing dryness of the mouth (xerostomia) and eyes (keratoconjunctivitis)
other secretory glands (nasopharynx, upper airway, vagina) may also be involved
extraglandular disease affecting the CNS, skin, kidneys, and muscles
increased risk for non-Hodgkin B-cell lymphoma (marginal-zonal type)
The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self antigen(s) expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues
autoantibodies to the ribonucleoprotein antigens SS-A (Ro) and SS-B (La)
Morphology
Pathology of the immune response. Immunologic deficiency syndromes. Transplantation immunity.
Immunodeficiency Disorders
Defects in B cells, T cells, complement, or phagocytic cells primary (genetic) secondary (acquired)
Congenital immunodeficiency disorders
B-cell disorders Recurrent encapsulated bacterial
infections (e.g., Streptococcus pneumoniae)
T-cell disorders Recurrent infections caused by
intracellular pathogens (fungi, viruses, protozoa)
Combined B- and T-cell disorders
Examples of Infections in ImmunodeficienciesPathogen Type T-Cell-Defect B-Cell Defect
Granulocyte Defect
Complement Defect
Bacteria Bacterial sepsis Streptococci, staphylococci, Haemophilus
Staphylococci, Pseudomonas
Neisserial infections, other pyogenic bacterial infections
Viruses Cytomegalovirus, Epstein-Barr virus, severe varicella, chronic infections with respiratory and intestinal viruses
Enteroviral encephalitis
Fungi and parasites
Candida, Pneumocystis carinii
Severe intestinal giardiasis
Candida, Nocardia, Aspergillus
Special features
Aggressive disease with opportunistic pathogens, failure to clear infections
Recurrent sinopulmonary infections, sepsis, chronic meningitis
PRIMARY Immunodeficiency Disorders
CHILDREN with repeated, often severe infections, cellular AND/OR humoral immunity problems, autoimmune defects
BRUTON (X-linked agammaglobulinemia) Common variable immunodeficiency IgA deficiency Hyper IgM DI GEORGE (THYMIC HYPOPLASIA) 22q11.2 SCID (Severe Combined Immuno Deficiency) WISKOTT-ALDRICH
thrombocytopenia and eczema Complement deficiencies
ADA=
ADENOSINE
DEAMINASE Bruton’s x-linked
agammaglobulemia NO tyrosine kinase (BTK
gene) Common variable
immunodeficiency Various genetic defects, both B and T cells
IgA deficiency Unknown
Hyper IgM CD40-L gene defect
DiGeorge: 22q11 deletion failure of development of 3rd
and 4th pharyngeal pouch. SCID
Early T-Cell failure
Primary Immunodeficiency Disorders
Disease Defect(s) Clinical FeaturesB-Cell Disorders
Bruton's agammaglobulinemia
Failure of pre-B cells to become matureB cells
Mutated tyrosine kinaseX-linked recessive disorder
Sinopulmonary infectionsMaternal antibodies protective from birth to age 6 months↓ Immunoglobulins
IgA deficiency Failure of IgA B cells to mature into plasma cells
Sinopulmonary infections, giardiasisAnaphylaxis if exposed to blood products that contain IgA↓ IgA and secretory IgA
Common variable immunodeficiency
Defect in B-cell maturation to plasma cells
Adult immunodeficiency disorder
Sinopulmonary infections, GI infections (e.g., Giardia), pneumonia, autoimmune disease↓ Immunoglobulins
T-Cell Disorder
DiGeorge syndrome Failure of third and fourth pharyngeal pouches to developThymus and parathyroids fail to develop
Hypoparathyroidism (tetany); absent thymic shadow on radiograph; PCP
Danger of GVH reaction
Combined B- and T-Cell Disorders
Severe combined immunodeficiency (SCID)
deaminase deficiency; adenine toxic to B and T cells, ↓ deoxynucleoside triphosphate precursors for DNA synthesisAutosomal recessive disorder
Defective CMI↓ ImmunoglobulinsTreatment: gene therapy, bone marrow transplant (patients with SCID do not reject allografts)
Wiskott-Aldrich syndrome Progressive deletion of B and T cellsX-linked recessive disorder
Symptom triad: eczema, thrombocytopenia, sinopulmonary infectionsAssociated risk of malignant lymphomaDefective CMI↓ IgM, normal IgG, ↑ IgA and IgE
Ataxia-telangiectasia Mutation in DNA repair enzymesThymic hypoplasiaAutosomal recessive disorder
Cerebellar ataxia, telangiectasias of eyes and skinRisk of lymphoma and/or leukemia↑ Serum α-fetoprotein
SecondaryImmunodeficiency Disorders
Autoimmune diseases (e.g., systemic lupus erythematosus)
Lymphoproliferative disorders (e.g., malignant lymphoma)
Infections (e.g., human immunodeficiency virus, HIV)
Immunosuppressive drugs (e.g., corticosteroids)
Radiotherapy
AIDS Acquired immunodeficiency syndrome
Etiology: HIV Pathogenesis: Infection, Latency, Progressive T-Cell loss Morphology:
Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load)
EPIDEMIOLOGY
HOMOSEXUAL (40%, and declining)
INTRAVENOUS DRUG USAGE (25%)
HETEROSEXUAL SEX (10% and rising)
OTHER MODES OF TRANSMISSION Vertical transmission - transplacental route, blood contamination
during delivery, breast-feeding Accidental needlestick
Most common mode of infection in health care workers Blood products
Risk per unit of blood is 1 per 2 million units of blood transfused.
Body fluids containing HIV Blood, semen, breast milk Virus cannot enter intact skin or mucosa
AIDS Acquired immunodeficiency
syndrome
Etiology RNA retrovirus
HIV-1 is the most common cause in the USA HIV-2 is the most common cause in developing countries.
Pathogenesis HIV envelope protein (gp120) attaches to the CD4 molecule
of T cells. HIV infects CD4 T cells, causing direct cytotoxicity. Infection of non-T cells
Can infect monocytes and macrophages in tissue (e.g., lung, brain)
Can infect dendritic cells in mucosal tissue Dendritic cells transfer virus to B-cell germinal follicles.
Macrophages and dendritic cells are reservoirs for virus. Loss of cell-mediated immunity
Reverse transcriptase Converts viral RNA into proviral double-stranded DNA DNA is integrated into the host DNA.
AIDS Acquired immunodeficiency
syndrome Acute phase
Mononucleosis-like syndrome 3 to 6 weeks after infection Latent (chronic) phase
Asymptomatic period 2 to 10 years after infection CD4 T-cell count greater than 500 cells/μL Viral replication occurs in dendritic cells (reservoir cells) in germinal follicles of
LN Early symptomatic phase
CD4 T-cell count 200 to 500 cells/μL Generalized lymphadenopathy Non-AIDS-defining infections - EBV-caused glossitis, oral candidiasis Fever, weight loss, diarrhea
AIDS Criteria
HIV-positive with CD4 T-cell count of 200 cells/μL or less or an AIDS-defining condition Most common AIDS-defining infections
Pneumocystis jiroveci pneumonia, systemic candidiasis AIDS-defining malignancies
Kaposi's sarcoma, Burkitt's lymphoma (EBV), primary CNS lymphoma (EBV) Causes of death
Disseminated infections (cytomegalovirus, Mycobacterium avium complex)
AIDS
1) PRIMARY INFECTION
2) LYMPHOID INFECTION
3) ACUTE SYNDROME
4) IMMUNE RESPONSE
5) LATENCY
6) AIDS
INFECTIONS of AIDS
Protozoal/Helminthic Cryptosporidium, Pneumocystis Carinii
Pneumonia, Toxoplasmosis Fungal
Candida Bacterial
TB, Nocardia, Salmonella Viral
CMV, HSV, VZ
PCP
CRYPTOSPORIDIUM
CASEATING GRANULOMA
CANCERS of AIDS
KAPOSI SARCOMA B-CELL LYMPHOMAS CNS LYMPHOMAS CERVIX CANCER, SQUAMOUS
CELL
AIDS Acquired immunodeficiency
syndrome
Immunologic abnormalities Lymphopenia (low CD4 T-cell count) Cutaneous anergy (defect in cell-mediated immunity) Hypergammaglobulinemia (due to polyclonal B-cell stimulation
by EBV) CD4:CD8 ratio <1
CD4 count and risk for certain diseases 700 to 1500: normal 200 to 500: oral thrush, herpes zoster (shingles), hairy
leukoplakia 100 to 200: Pneumocystis jiroveci pneumonia, dementia Below 100: toxoplasmosis, cryptococcosis, cryptosporidiosis Below 50: CMV retinitis, Mycobacterium avium complex,
progressive multifocal leukoencephalopathy, primary central nervous system lymphoma
Pregnant women with AIDS Treatment with a reverse transcriptase inhibitor reduces
transmission to newborns to less than 8%.
Types of grafts Autograft (i.e., self to self)
Associated with the best survival rate Syngeneic graft (isograft)
Between identical twins Allograft
Between genetically different individuals of the same species
Xenograft Between two species Example-transplant of heart valve from pig to
human
Types of transplants Cornea
Best allograft survival rate Danger of transmission of Creutzfeldt-Jakob
disease Kidney
Better survival with kidney from living donor than from cadaver
Bone marrow Graft contains pluripotential cells that repopulate
host stem cells Host assumes donor ABO group Danger of graft-versus-host reaction and
cytomegalovirus infection
Transplantation Immunology
Transplantation rejection involves a humoral or cell-mediated host response against MHC antigens in the donor graft.
There are two main mechanisms by which the host immune system recognizes and responds to the MHC molecules on the graft
Direct recognition donor class I and class II MHC
antigens on APCs in the graft are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively.
CD4+ cells proliferate and produce cytokines (e.g., IFN-γ), which induce tissue damage by a local delayed-hypersensitivity reaction.
CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells.
Indirect recognition graft antigens are displayed by host
APCs and activate CD4+ T cells, which damage the graft by a local delayed-hypersensitivity reaction and stimulate B lymphocytes to produce antibodies.
Direct pathway Indirect pathway
Types of rejection
On the basis of the mechanisms involved, the resulting morphology, and the tempo of the various processes, rejection reactions have been classified as: Hyperacute (minutes)
AG/AB reaction of vascular endothelium
Acute (days months) cellular (INTERSTITIAL infiltrate) and humoral
(VASCULITIS) Chronic (months)
slow vascular fibrosis
Types of rejection
Hyperacute rejection Irreversible reaction occurs
within minutes. Pathogenesis
ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed against donor antigens in vascular endothelium
Type II hypersensitivity reaction Pathologic finding
Vessel thrombosis Example-blood group A person
receives a blood group B heart.
Types of rejection Acute rejection
Most common transplant rejection Reversible reaction that occurs
within days to weeks Type IV cell-mediated
hypersensitivity CD4 T cells release cytokines,
resulting in activation of host macrophages, proliferation of CD8 T cells, and destruction of donor graft cells.
Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury
Antibody-mediated type II hypersensitivity reaction Cytokines from CD4 T cells promote
B-cell differentiation into plasma cells, producing anti-HLA antibodies that attack vessels in the donor graft.
Vasculitis with intravascular thrombosis in recent grafts
Intimal thickening with obliteration of vessel lumens in older grafts
Types of rejection
Chronic rejection Irreversible reaction
that occurs over months to years
Pathogenesis probably caused by
T-cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis.
Blood vessel damage with intimal thickening and fibrosis
Factors enhancing graft viability
ABO blood group compatibility between recipients and donors
Absence of preformed anti-HLA cytotoxic antibodies in recipients People must have previous exposure to blood
products to develop anti-HLA cytotoxic antibodies.
Close matches of HLA-A, -B, and -D loci between recipients and donors
Transplantation of Hematopoietic Cells
Graft-versus-host (GVH) reaction
Causes Potential complication in bone marrow and liver
transplants Potential complication in blood transfusions given to
patients with a T-cell immunodeficiency and newborns.
Pathogenesis Donor T cells recognize host tissue as foreign and
activate host CD4 and CD8 T cells. Clinical findings
Bile duct necrosis (jaundice) Gastrointestinal mucosa ulceration (bloody diarrhea) Dermatitis