General Pathology

Basic Principles of Cellular and Organ Pathology

Inflammation - IV

Jaroslava Dušková

Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague

CD3

Immune Disorders

Diseases Jaroslava Duško

vá

Immune Disorders Diseases – table of contents

Immune Deficiency Diseases primary – inborn

NG disorders

thymic hypoplasia

T-lymphopenia

Bruton´s agamaglobulinemia

isolated IgA deficiency

complement deficiency

secondary – acquired HIV-AIDS

neutropenia

leukemia

vascular - DM, ischemia –atherosclerosis

malnutrition

aging

Increased – Hypersensitivity –Allergy

I. anaphylactic

II. cytotoxic

III. immune complexes

IV. cell mediated (delayed) T-cell mediated cytotoxicity

Self oriented – Autoimmune Diseases Autoimmunity – definition,

function

Mechanisms of autoimmune reaction prevention

Autoimmune diseases –representatives systemic

organ related

Jaroslava Duško

vá

Defenses Against Infection – 1/3

Surface

barriers: skin, conjunctiva, mucous membranes

mechanical removal: shedding, tears, mucus,

ciliary action, coughing, salivation, swallowing,

urination, defecation

normal bacterial flora

chemical inhibitors: gastric acid, lactic acid, fatty

acids,bile salts, Tamm- Horsfall protein..

antimicrobial substances: lysozym, secretory IgA

Jaroslava Duško

vá

Defenses Against Infection – 2/3

Nonspecific resistance factors fever, interferon, complement, lysozyme, C-reactive

protein, lactoferrin, α1- antitrypsin

Inflammation- soluble factors clotting system –Hageman fc. (XII)

complement system: chemotactic fc, anaphylatoxins

kinin system: bradykinin

Inflammation- phagocytes circulating: neutrophils, eosinophils, monocytes, macrophages

fixed: alveoli, spleen, liver, bone marow, brain

Jaroslava Duško

vá

Defenses Against Infection – 3/3

Immune response

humoral: B-cells, plasma cells, immunoglobulins

cell-mediated: T-cells, lymphokinsJaroslava Duško

vá

Primary – inborn - genetically determined

NG disorders

Thymic hypoplasia – Di George syndrome

T-lymphopenia

Bruton´s agamaglobulinemia (X-linked, BTK)

Isolated IgA deficiency

Complement deficiency

Secondary – acquiredHIV-AIDS

Neutropenia

Leukemia

Vascular - DM, ischemia – atherosclerosis

Malnutrition

Aging

Immune Deficiency Diseases

Jaroslava Duško

vá

Primary – inborn - genetically determined

NG disorders

Thymic hypoplasia – Di George syndrome

T-lymphopenia

Bruton´s agamaglobulinemia (X-linked, BTK)

Isolated IgA deficiency

Complement deficiency

Secondary – acquired HIV-AIDS

Neutropenia

Leukemia

Vascular - DM, ischemia – atherosclerosis

Malnutrition

Aging

Immune Deficiency Diseases

- clinical manifestations

Increased susceptibility to

• infections

•tumoursJaroslava Duško

vá

Hypersensitivity - types

I. anaphylactic astma IgE

II. cytotoxic erythroblastosis IgG, IgM

III. immune complexes SLE, GN, Ag+AB+C

IV. cell mediated (delayed) tbc, contact

dermatitis – T-cell mediated cytotoxicityJarosla

va Dušková

Hypersensitivity - types

I. anaphylactic (astma) Th2 activation-

production of IgE – degranulation of mast

cells – vasoactive amins- hypersensitivity

reaction

Jaroslava Duško

vá

Hypersensitivity - types

II. cytotoxic erythroblastosis, pemphigus

vulgaris, myasthenia gravis, DM I, pernicious

anemia… IgG, IgM

target antigens on cell surface

destruction of cells

derangement of function

Jaroslava Duško

vá

Hypersensitivity - types

III. immune complexes SLE, GN, polyarteritis

nodosa… Ag+AB+C

depositions in blood vesels

vascular complicationsJarosla

va Dušková

Erythema multiforme

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Jaroslava Duško

vá

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Erythema multiforme

Jaroslava Duško

vá

Hypersensitivity - types

IV. T -cell mediated (delayed) tbc, contact

dermatitis, RA, MS, DM I, HT,

cytokine mediated inflammation - CD4 T

cells – delayed response, macrophages are

the main effectors

direct cytolysis CD8 T cells

Jaroslava Duško

vá

Contact

stomatitis

unknown allergen

Jaroslava Duško

vá

Autoimmunity

lack of self-tolerance

Jaroslava Duško

vá

Autoimmunity

constant activity in

organogenesis

regeneration

metalaxiaJarosla

va Dušková

Autoimmune Diseases

Def.:

loss of self-tolerance

resulting into damage

of organ /tissueJarosla

va Dušková

Self x Non-SelfMechanisms Preventing Antiself

Reactivity:

clonal deletion - thymus

clonal anergy – APC „off signal“

peripheral suppresion – Ts CD8+

Protection from protectors….

Jaroslava Duško

vá

Activation of Apoptosis

Jaroslava Duško

vá

Inflammation – autoimmuneSystemic autoimmune diseases

DISEASE

SLE

RA

Sjögren dis.

Syst. sclerodermia

Dermato–polymyositis

Prim. vasc. syndromes

ANTIBODY

ANA, ENA

collag. II, Fc –Ig

(rheum. factor)

ANA,ENA

ENA (Scl–70)

ENA (Jo–1)

ANCA

Jaroslava Duško

vá

SLE - Lupus

erytematodes

disseminatus

Jaroslava Duško

vá

Lupus erytematodes disseminatus

VASCULITIS

skin – butterfly rash, discoid erythema

mucose membranes ulcers

heart- Libman-Sacks endocarditis

arthritis

serositis

hemopoietic disorders – hemolytic anemia, leuco-lympho- thrombocyto- penia

kidney – glomerulonephritis

CNS – seizures, psychosis (vascular etiology?)

SLE

Jaroslava Duško

vá

Jaroslava Duško

vá

SLE. Papillary necroses – vasculitis (Bilddatenbank Basel)

Jaroslava Duško

vá

SLE GN . Man 29. (Bilddatenbank Basel)

Jaroslava Duško

vá

Rheumatoid arthritis

Jaroslava Duško

vá

Rheumatoid arthritis- polyarthritis progressiva primaria chronica

adult women mainly

small joints

morning stiffness

dysfigering, pain, ankylosis

+ tendovaginitis, iridocyclitis, vasculitis, lung fibrosis

serum rheumatoid factor – IgM x Fc IgG –immunocomplexes

complication (potentially killing)

Jaroslava Duško

vá

Amyloidosis renis

Jaroslava Duško

vá

Amyloid Diagnosis Immunohistochemistry

Jaroslava Duško

vá

Def.:

a group of autoimmune conditions

characterized by T-lymphocyte

mediated sialo- & dacryoadenitis

----------

women predilection

sicca (dry) syndrome

Sjögren´s syndrome

Jaroslava Duško

vá

Jaroslava Duško

vá

Classification:

primary: keratoconjunctivitis sicca,

sialoadenitis, no co-existing systemic a-i

diseases

secondary: accompanying rheumatoid

arthritis, SLE, dermatomyositis….

Sjögren´s syndrome

Jaroslava Duško

vá

T.E.Daniels, Th.B. Aufdemorte, J.S.Greenspan:

Histopathology

of Sjögren´s syndrome.

s. 41-52, in:

N. Talal, H.M. Moutsopoulos, S.S.Kassan:

Sjögren´s syndrome. Clinical and

immunological aspects. Springer Vrlg, Berlin, Heidelberg, New York, London, Paris, Tokyo 1987, 299ss.

Jaroslava Duško

vá

Focus Score

Morphometric representation of focally

accented chronic sialoadenitis

focus – agregate of 50 and more

lymphocytes (defined 1968) Jarosla

va Dušková

Sicca syndrome

Jaroslava Duško

vá

Jaroslava Duško

vá

meandr

scaning

FS ≥ 1

Jaroslava Duško

vá

Focus Score morphometry result table

Jaroslava Duško

vá

Lichen planus

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Jaroslava Duško

vá

Lichen planus

fibrinogen Ab in BM

Mucous Membrane

Pemphigoid IgG, C3 along BM

Pemphigus vulgaris IgG

Erythema multiforme IgM,C3

deep dermis - perivascular

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Jaroslava Duško

vá

Inflammation – autoimmune: Organ autoimmune diseases

Skin (& mucous membranes)

ANTIBODY

intercel. epith. matrix(desmoglein 3)

basement membrane

of epidermis

DISEASE

pemphigus

pemphigoidJarosla

va Dušková

Mucous membrane

pemphigoid

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Jaroslava Duško

vá

Pemphigus vulgaris

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Jaroslava Duško

vá

Pemphigus vulgaris

Jaroslava Duško

vá

Pemphigus

vulgaris

J.P.Sapp et al. Contemporary maxillofacial pathology.

2nd ed. Mosby 2004

Jaroslava Duško

vá

Pemphigus vulgaris

Jaroslava Duško

vá

Sclerodermia

Systemic

Sclerosis

SS

Jaroslava Duško

vá

SS

Sclerodermia

Jaroslava Duško

vá

Sclerodermia - vasculitis

Jaroslava Duško

vá

Inflammation – autoimmuneOrgan autoimmune diseases – GIT

ANTIBODY against

mitochondrie

membr. hct., cytosol

gliadin

DISEASE

primary billiary

cirrhosis

CAH

gluten

enteropathy

Jaroslava Duško

vá

Celiac Sprue

Jaroslava Duško

vá

man 27 yrs B 2138/06

4 pieces from D3 announced

3 pieces diam. 1-2mm found

clin. dg. susp. celiakia, diff. dg. lambliasis

Jaroslava Duško

vá

Jaroslava Duško

vá

Jaroslava Duško

vá

Jaroslava Duško

vá

CD 3

Jaroslava Duško

vá

CD 3

Jaroslava Duško

vá

CD 3

Jaroslava Duško

vá

Histopathology Report

mild shortening & widening of villi

intraepit. lymphocytes > 40/100 enterocytes

lamblie not found

Conclusion: histopathology changes

supporting clinical dg. suggested - celiac

sprue - type 3a of Marsh´ - Oberhuber´s

classification

Jaroslava Duško

vá

Marks, DJB, Harbord, MWN, Mac Allister R. et al.:

Impotent immune System: An Underlying

Problem in Crohn´s Disease. Lancet 2006, 367, 668-78

in patients with Crohn´s an impaired acute

inflammatory response – 79% reduction in

the number of neutrophils and interleukin 8

in ulcerative colitis initiation of inflammation

normal, resolution delayedJarosla

va Dušková

m. Crohn

Jaroslava Duško

vá

m. Crohn

Jaroslava Duško

vá

Inflammation – autoimmuneOrgan autoimmune diseases – endocrine

ANTIBODY

TGB, microsomes

pancreas cells

insulin

ins. receptors

adrenal microsomes

TSH rec.

DISEASE

GB, HT

DM I

I–res. DM

I–res. DM

Adison dis.

GB

Jaroslava Duško

vá

Thyroid m.G-B

Jaroslava Duško

vá

Hashimoto Thyroiditis

Jaroslava Duško

vá

Hashimoto

Thyroiditis

Jaroslava Duško

vá

Epinephritis chronica

Jaroslava Duško

vá

m. Adisoni

atrophy

tbc

tumour

Jaroslava Duško

vá

Inflammation – autoimmuneOrgan autoimmune diseases – CNS

ANTIBODY

acetylcholin rec.

basic myelin protein

DISEASE

myasthenia

gravis

disseminated

sclerosisJaroslava Duško

vá

Sclerosis cerebrospinalis multiplex disseminata – multiple sclerosis - MS

chronic autoimmune demyelinating encephalitis

Jaroslava Duško

vá

Sclerosis cerebrospinalis multiplex disseminata- virus infection influence (morbilli, herpes, EB)

…bacteria?...

Pathogenesis

interaction of the macroorganism

and virus – limited antibody production

(only 10-20% produced viruses are virulent)

virus mutation & immunosupresion

(age, pregnancy, stress, other diseases….)

Jaroslava Duško

vá

MS – viral influence (2)

Pathogenesis

infection of endothelia – microangiitis

blood-brain- barrier disorder

serum & CSF CD4, CD8

(miror image to AIDS)

Sclerosis cerebrospinalis multiplex disseminata

- virus infection influence 2.

Jaroslava Duško

vá

Sclerosis

cerebrospinalis

multiplex disseminata

immobility/spasticity

anesthesia

sight disorders

incontinence

cognitive dysfunction

pain

depresssion

Pons Varoli – lux. modř

Jaroslava Duško

vá

Immune Disorders Diseases

Morphology

alteration up to necrosis

NG + lymphoplasmocellular infiltration

fibrosis

Prognosis

important in terms of both morbidity and

mortality – possible lethal outcome

Jaroslava Duško

vá

Rejection of Transplants - pathways

Allografts – MHC molecules recognized

mainly on the graft DCs:

direct recognition by the host CD8+T cells –endothelial damage - acute fibrinoid necrosis- thrombosis-

ischemia

indirect recognition by the host CD4+ T cells –

AB mediated

Jaroslava Duško

vá

Rejection of Transplants - effectors

hyperacute - hours – pre-existing ABs

acute – days to weeks CD4+ and CD8+

T cells

chronic – months – productive

endarteritis – T cell secretion of cytokins

chronic

acute

Jaroslava Duško

vá

Graft Versus Host Disease - GVHD

cause - immunocompetent donor T cells in:

hematopoietic stem cell transplantation

organs rich in lymphoid cells – liver

non-irradiated blood transfusion

manifestation: acute – days to weeks – epithelial necroses –

GIT, skin – potentially lethal

chronic – months - syst. sclerosis - like skin

lesions, autoimmune disorders

Jaroslava Duško

vá

Jaroslava Duško

vá