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Diseases of IMMUNITY

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OBJECTIVES Differentiate between the concepts ofInnate and Adaptive immunity

Visually recognize and understand the basic

roles of lymphocytes, macrophages,dendritic cells, NK cells in the immune saga

Understand the roles of the major cytokines

in immunity Differentiate and give examples of the four

(4) different types of hypersensitivity

reactions

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OBJECTIVES Know the common features of autoimmune

diseases, and the usual four (4) mainfeatures (Etiology, Pathogenesis,Morphology, and Clinical Expression) of

Systemic Lupus Erythematosus,Rheumatoid Arthritis, Sjgrens, SystemicSclerosis (Scleroderma), Mixed Connective

Tissue Disease, and Poly- (aka, Peri-) -arteritis Nodosa Differentiate between Primary (Genetic) and

Secondary (Acquired) Immunodeficiencies

http://66.99.255.20/cms/anatomy/minarcik/Disease.dochttp://66.99.255.20/cms/anatomy/minarcik/Disease.dochttp://66.99.255.20/cms/anatomy/minarcik/Disease.dochttp://66.99.255.20/cms/anatomy/minarcik/Disease.doc

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OBJECTIVES Understand the usual four (4) main featuresof AIDS, i.e., etiology, pathogenesis,

morphology, clinical expression Understand the usual four (4) main features

of Amyloidosis

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IMMUNITY INNATE(present before

birth, NATURAL)

ADAPTIVE(developedby exposure to pathogens,or in a broader sense,antigens not recognized by

the MHC)

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MHCMajorHistocompatibility Complex

A genetic LOCUS on Chromosome 6,

which codes for cell surface compatibility Also called HLA (Human LeukocyteAntigens) in humans and H-2 in mice

Its major job is to make sure all self cellantigens are recognized and tolerated,because the general rule of the immunesystem is that all UN-recognized antigens

will NOT be tolerated

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INNATE IMMUNITY BARRIERS

CELLS: LYMPHOCYTES,

MACROPHAGES, PLASMA CELLS,NK CELLS

CYTOKINES/CHEMOKINES

PLASMA PROTEINS:Complement, Coagulation Factors

Toll-Like Receptors, TLRs

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ADAPTIVE

IMMUNITYCELLULAR,i.e.,directcellular reactions toantigens

HUMORAL,i.e.,

antibodies

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CELLS of the IMMUNE SYSTEM

LYMPHOCYTES, T LYMPHOCYTES, B

PLASMA CELLS (MODIFIED B CELLS) MACROPHAGES, aka HISTIOCYTES,

(APCs, i.e., Antigen Presenting Cells)

DENDRITIC CELLS (APCs, i.e., AntigenPresenting Cells) NK (NATURAL KILLER) CELLS

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L

Y

M

P

H

S

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ANY ROUND CELL WITH RATHERDENSE STAINING NUCLEUS AND

MINIMAL CYTOPLASM INCONNECTIVE TISSUE, A BITBIGGER THAN AN RBC, IS A

LYMPHOCYTEUNTIL PROVEN OTHERWISE

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MACROPHAGE

aka

HISTIOCYTE

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MACROPHAGES areMONOCYTES that have comeout of circulation and havegone into tissue

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MACROPHAGES, TEM, SEM

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ANY CELL MIXED IN WITH LYMPHOCYTES BUT HASA LARGER MORE OPEN, i.e., vesicular, LESSDENSE, LESS CIRCULAR NUCLEUS WITH MORE

CYTOPLASM IS A

MACROPHAGEUNTIL PROVEN OTHERWISE

ALMOST ALL GRANULAR or PIGMENTED

CELLS IN CONNECTIVE TISSUE AREMACROPHAGES. GRANULOMAS, GIANT CELLS,ARE CHIEFLY MACROPHAGES ALSO.

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1) ROUND NUCLEUS

2) OVOID CYTOPLASM

3) PERIPHERAL CHROMATIN

4) CLEAR ZONE BETWEEN NUCLEUS AND WIDER LIP OF

CYTOPLASM

PLASMA CELLS

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NK CELLS

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GENERAL SCHEME of

CELLULAR EVENTS APCs (Macrophages, DendriticCells)

T-Cells (Control Everything)CD4REGULATORS (Helper)CD8EFFECTORS

B-Cells Plasma CellsABs NK Cells

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CYTOKINES MEDIATE INNATE (NATURAL)

IMMUNITY, IL-1, TNF, INTERFERONS

REGULATE LYMPHOCYTE GROWTH(many interleukins, ILs)

ACTIVATE INFLAMMATORY CELLS STIMULATE HEMATOPOESIS,

(CSFs, orColony Stimulating Factors)

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MHCMajorHistocompatibility Complex

A genetic LOCUS on Chromosome 6,

which codes for cell surface compatibility Also called HLA (Human LeukocyteAntigens) in humans and H-2 in mice

Its major job is to make sure all self cellantigens are recognized and tolerated,because the general rule of the immunesystem is that all UN-recognized antigens

will NOT be tolerated

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MHC MOLECULES

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MHC MOLECULES(Gene Products)

I (All nucleated cells and platelets), cell surfaceglycoproteins, ANTIGENS

II(APCs, i.e., macs and dendritics, lymphs),cell surface glycoproteins, ANTIGENS

III Complement System Proteins

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IMMUNE SYSTEM DISORDERSWHAT CAN GO WRONG?

HYPERSENSITIVITY REACTIONS, I-IV

AUTO-IMMUNE DISEASES, akaCOLLAGEN DISEASES (BAD TERM)

Inflammation NOT due to externalpathogens, MHC failure.

IMMUNE DEFICIENCY SYNDROMES,

IDS: PRIMARY (GENETIC)

SECONDARY (ACQUIRED)

HYPERSENSITIVITY

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HYPERSENSITIVITY

REACTIONS (4) I (Immediate Hypersensitivity)

II (Antibody MediatedHypersensitivity)

III (Immune-Complex MediatedHypersensitivity)

IV (Cell-Mediated Hypersensitivity)

T I

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Type IIMMEDIATE HYPERSENSITIVITY

Immediate means seconds to minutes Immediate Allergic Reactions, which may

lead to anaphylaxis, shock, edema, dyspneadeath 1) Allergen exposure 2) IMMEDIATE phase: MAST cell

DEgranulation, vasodilatation, vascularleakage, smooth muscle (broncho)-spasm

3) LATE phase (hours, days): Eosinophils,PMNs, T-Cells

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TYPE II HYPERSENSITIVITYANTIBODY MEDIATED IMMUNITY

ABs attach to cell surfaces OPSONIZATION (basting the turkey)

PHAGOCYTOSIS COMPLEMENT FIXATION (cascade of

C1q, C1r, C1s, C2, C3, C4, C5.. ) LYSIS (destruction of cells by

rupturing or breaking of the cellmembrane)

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TYPE II DISEASES Autoimmune Hemolytic Anemia, AHA Idiopathic Thrombocytopenic Purpura,

ITP

Goodpasture Syndrome (Nephritis andLung hemorrhage)

Rheumatic Fever

Myasthenia Gravis Graves Disease Pernicious Anemia, PA

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TYPE III HYPERSENSITIVITYIMMUNE COMPLEX MEDIATED

Antigen/Antibody Complexes Where do they go?

Kidney (Glomerular Basement Membrane)

Blood Vessels Skin Joints (synovium)

Common Type III Diseases- SLE (Lupus),Poly(Peri)arteritis Nodosa,Poststreptococcal Glomerulonephritis,Arthus reaction (hrs), Serum sickness

(days)

TYPE IV HYPERSENSITIVITY

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TYPE IV HYPERSENSITIVITYCELL-MEDIATED (T-CELL)

DELAYED HYPERSENSITIVITY Tuberculin Skin Reaction

DIRECT ANTIGENCELL CONTACT GRANULOMA FORMATION

CONTACT DERMATITIS

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SUMMARY I Acute allergic reaction

II Antibodies directed against cellsurfaces

III Immune complexes

IV Delayed Hypersensitivity, e.g., Tb

skin test RENAL

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RENALTRANSPLANT REJECTION

HYPERACUTE (minutes) : AG/ABreaction of vascular endothelium

ACUTE (days months): cellular(INTERSTITIAL infiltrate, possibly monos)and humoral (VASCULITIS)

CHRONIC (months): slow vascularfibrosis

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ACUTE CELLULAR (T) ACUTE HUMORAL

CHRONIC

AUTO IMMUNE DISEASES

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AUTO-IMMUNE DISEASES

Failure of SELF RECOGNITION Failure of SELF TOLERANCE

TOLERANCE

CENTRAL (Death of self reactive lymphocytes)PERIPHERAL (anergy, suppression by T-cells,

deletion by apoptosis, sequestration (Ag masking))

STRONG GENETIC PREDISPOSITION OFTEN RELATED TO OTHER AUTOIMMUNE

DISEASES

OFTEN TRIGGERED BY INFECTIONS

CLASSIC AUTOIMMUNE

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CLASSIC AUTOIMMUNE

DISEASES (SYSTEMIC)LUPUS (SLE) Systemic LupusErythematosus

RHEUMATOID ARTHRITIS

SJGREN SYNDROME

SYSTEMIC SCLEROSIS (scleroderma)

MCD (Mixed Connective Tissue Dis.)

Poly (Peri-) arteritis nodosa

CLASSIC AUTOIMMUNE

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CLASSIC AUTOIMMUNE

DISEASES (LOCAL) HASHIMOTO THYROIDITIS AUTOIMMUNE HEMOLYTIC ANEMIA

MULTIPLE SCLEROSIS AUTOIMMUNE ORCHITIS

GOODPASTURE SYNDROME

AUTOIMMUNE THROMBOCYTOPENIA (ITP)

PERNICIOUS ANEMIA

INSULIN DEPENDENT DIABETES MELLITUS

MYASTHENIA GRAVIS

GRAVES DISEASE

N B

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N.B. The list of diseasesproven to beautoimmune grows

by leaps and boundsevery year!!!

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H R

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O

M

O

S

P

E

C

K

I

M

N

U

C

L

E

O

L

A

R

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SLE, SKIN SLE, GLOMERULUS

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TABLE 6-10 -- Clinical and Pathologic Manifestations of Systemic LupusErythematosus

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Erythematosus

Clinical Manifestation

Prevalence

inPatients, %

Hematologic 100

Arthritis 90Skin 85Fever 83Fatigue 81Weight loss 63Renal 50Central nervous system 50Pleuritis 46Myalgia 33Pericarditis 25Gastrointestinal 21Raynaud phenomenon 20Ocular 15Peripheral neuropathy 14

MORE SYSTEMIC

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MORE SYSTEMIC

AUTOIMMUNEDISEASES RHEUMATOID ARTHRITIS SJGREN SYNDROME

SCLERODERMA (SYSTEMICSCLEROSIS)

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NORMAL Bi-Layered

Synovium

Destructive

Rheumatoid Synovitis

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SJGRENSYNDROME

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SCLERODERMA

(SYSTEMIC SCLEROSIS)

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SYSTEMIC SCLEROSIS

(SCLERODERMA) M RE AUT IMMUNE

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M RE AUT IMMUNEDISEASES (LOCAL)

HASHIMOTO THYROIDITIS (anti-thyroglob, anti-microsome)

AUTOIMMUNE HEMOLYTIC ANEMIA (AHA) (anti-RBC)

MULTIPLE SCLEROSIS (anti-MBP)

AUTOIMMUNE ORCHITIS (Anti-germ cell)

GOODPASTURE SYNDROME (anti-GBM Abs)

AUTOIMMUNE THROMBOCYTOPENIA (ITP) (anti-plats)

PERNICIOUS ANEMIA (anti-IF, anti-parietal cell Abs) INSULIN DEPENDENT DIABETES MELLITUS (I) (anti-islets)

MYASTHENIA GRAVIS (anti-NM-junction)

GRAVES DISEASE (anti-TSHR-Abs cause activation)

I D fi

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ImmunoDefiency

Syndromes (-IDS)PRIMARY (GENETIC)(P-IDS?)

SECONDARY(

ACQUIRED) (A-IDS)

PRIMARY

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PRIMARY CHILDREN with repeated, often severeinfections, cellular AND/OR humoral

immunity problems, autoimmune defects BRUTON (X-linked agammaglobulinemia) COMMON VARIABLE

IgA deficiency Hyper -IgM DI GEORGE (THYMIC HYPOPLASIA) 22q11.2

SCID (Severe Combined Immuno Deficiency) .with thrombocytopenia and eczema

(WISKOTT-ALDRICH)

COMPLEMENT DEFICIENCIES

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ADA=

ADENOSINE

DEAMINASE

Examples of Infections in ImmunodeficienciesGran loc te

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Pathogen Type T-Cell-Defect B-Cell DefectGranulocyte

Defect Complement DefectBacteria Bacterial sepsis Streptococci,

staphylococci,

Haemophilus

Staph,Pseudomo

nas

Neisserialinfections,otherpyogenicinfections

Viruses Cytomegalovirus,Epstein-Barr virus,

severe varicella,chronic infectionswith respiratory andintestinal viruses

Enteroviral

encephalitis

Fungi andparasites

Candida, Pneumocystis

carinii

Severe intestinal

giardiasis

Candida,

Nocardia,Aspergillus

Special featuresAggressive disease with

opportunistic pathogens,

failure to clear infections

Recurrent

sinopulmonary

infections, sepsis,

chronic meningitis

(A)IDS

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(A)IDS(SECONDARY IDS) Etiology: HIV Pathogenesis: Infection, Latency,

Progressive T-Cell loss

Morphology: MANY

ClinicalExpressions: Infections,Neoplasms, Progressive Immune Failure,

Death, HIV+, HIV-RNA (Viral Load)

EPIDEMIOLOGY

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EPIDEMIOLOGY HOMOSEXUAL (40%, and

declining)

INTRAVENOUS DRUGUSAGE (25%)

HETEROSEXUAL SEX (10%and rising)

ETIOLOGY

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ETIOLOGY

PATHOGENESIS

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PATHOGENESIS

ATTACHING BUDDING

PATHOGENESIS

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PATHOGENESIS

EARLY BUDDING

PATHOGENESIS

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PATHOGENESIS

LATE BUDDING

PATHOGENESIS

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PATHOGENESIS

MATURE NEW VIRIONS

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REVERSETRANSCRIPTASE

The enzyme reverse transcriptase(RT) is used by retroviruses totranscribe their single-stranded

RNA genome into single-strandedDNA and to subsequentlyconstruct a complementary strand

of DNA, providing a DNA doublehelix capable of integration intohost cell chromosomes.

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PATHOGENESIS

PATHOGENESIS

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PATHOGENESIS

1) PRIMARY INFECTION2) LYMPHOID INFECTION

3) ACUTE SYNDROME

4) IMMUNE RESPONSE

5) LATENCY

6) AIDS

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GENERAL IMMUNE

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GENERAL IMMUNEABNORMALITIES

LYMPHOPENIA DECREASED T-CELL

FUNCTION B-CELL ACTIVATION,POLYCLONAL

ALTEREDMONOCYTE/MACROPHAGE

FUNCTION

INFECTIONS

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INFECTIONS Protozoal/Helminthic:Cryptosporidium, PCP

(Pneumocystis Carinii (really

Jiroveci) Pneumonia),Toxoplasmosis

Fungal: Candida, and the usual 3 Bacterial:TB, Nocardia, Salmonella

Viral: CMV HSV VZ(Herpes Family)

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PCP

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CRYPTOSPORIDIUM

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CASEATING GRANULOMA

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CONGO RED STAIN, WITHOUT,and WITH, POLARIZATION

AMYLOID ASSOCIATIONS

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AMYLOID ASSOCIATIONS

PLASMA CELL DYSCRASIAS, i.e.,MULTIPLE MYELOMA CHRONIC GRANULOMATOUS

DISEASE, e.g., TB HEMODIALYSIS HEREDOFAMILIAL

LOCALIZED ENDOCRINE MEAs (Multiple Endocrine

Adenomas)