14,15

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.

http://en.wikipedia.org/wiki/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


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


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


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


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


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.


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

CRYPTOSPORIDIUM

CASEATING GRANULOMA

CANCERS of AIDS

KAPOSI SARCOMA B-CELL LYMPHOMAS CNS LYMPHOMAS CERVIX CANCER, SQUAMOUS

CELL


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

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