Immune disorders

immunity & immune disorders - extreme

importance (comparable to bacteriology at
the early 20th cent.)
new diseases, immunological etiology in
"old" diseases, immunotherapy -
considerable amount oI medical inIormation
immune system - important Ior survival
increased or decreased immunity - disease
Introduction
humoral & cellular immunity
B-lymphocytes - plasma cells - Ig A, M, G, E, D
lymph nodes - cortex - germinal centers
T-lymphocytes (60-70 in peripheral blood)
lymph nodes - paracortex
subspecialization (helper, suppressor, killer,
natural killer)
Introduction
Macrophages
Antigen-presenting cells - dendritic cells,
Langerhans cells (skin)
MHC system
HLA complex antigens - ability to recognize own
Ag Irom Ioreign ones
importance in transplantation - rejection
(destruction oI the graIt by host)
. Immune mechanisms oI tissue
damage
immune response (both humoral&cellular)
Ag (both exogenous&endogenous)
inappropriate - hypersensitive reaction
allergy - 4 types
I. Anaphylactic type
quickly developing aIter contact oI Ag (allergen)
with Ab
previous exposition!
B-cells - IgE
mediated through histamine, leucotriens,
prostaglandins (granules oI mast cells &
basophilic leucocytes)
increase oI vascular permeability, vasodilatation,
bronchoconstriction, increased mucoproduction
local reaction - skin or mucosa
bee sting, Iood allergy, hay Iever (pollinosis),
asthma bronchiale, urticaria (hives)
Iamiliar predisposition - atopy
systemic reaction
parenteral administration oI Ag (e.g. antiserum,
drug-ATB) - systemic anaphylaxis -~ anaphylactic
shock
minutes - itching, rush, redding oI skin
breathing problems, abdominal pain, vomiting,
diarrhea
during several min - death due to collapse oI
circulation
II. Antibody dependent type
antigens - autologous (own) or homologous
(another human)
incompatible blood transIusion - destruction
oI RBCs
Rh-incompatibility - Ietal erythroblastosis
(anti-Rh Ab)
III. Immune complex diseases
Iormation oI Ag-Ab complexes (immune
complexes)
activation oI complement and accumulation oI
polymorphonuclear leucocytes
acute inIlammation oI tissues
e.g. serum sickness - repeated exposure to animal
(equine) serum (antitetanic)
immuncomplexes are deposited in tissues -
inIlammation
vessel wall - acute necrotizing vasculitis
(Iibrinoid necrosis) - thrombosis - ischemic
necrosis
vessel wall replaced by smudgy, pink
material
local Iorm oI IS - Arthus reaction (animal
model - skin lesion) - localized area oI
tissue necrosis resulting Irom immune
complex vasculitis - Iarmer's lungs (molds
on hay)
some types oI glomerulonephritis
systemic lupus erythematodes (SLE)
IV. Delayed type oI hypersensitivity
(tuberculin-type) - cell mediated
cellular immunity - T-cells&histiocytes
Irequently granulomatous reaction (epithelioid
cells)
TBC, syphilis, leprosy
e.g. tuberculin reaction - Mantoux test
person previously exposed to TBC develops aIter
intradermal injection oI Ag skin induration
maniIestation aIter 8-2 h, maximum 2-7 weeks
Transplantation rejection
transplantation:
- autologous (own)
- homologous (alogenic) - human tissue
- heterologous - animal tissue (pig skin,
ovine pericardium)
both humoral and cellular immunity - HLA
system
Rejection reactions (e.g. renal
graIt)
hyperacute (Ab mediated) - widespread
arteriolitis, arteritis, thrombosis - ischemic
necrosis (minutes-hours)
acute (cell mediated) - lymphocytic
inIiltration, vasculitis, tubulitis, edema
(days-months) - biopsy!!! (days-months)
chronic - vascular changes - sclerosis,
intimal Iibrosis (months-years)
GraIt versus host disease
(GVHD)
in transplantations oI allogenic
hematopoietic cells
immunologically competent donor cells
transplanted into immunologically
compromized recipient
donor's T-cells react against "Ioreign"
recipient's tissues
liver, skin, gut
2. Autoimmune diseases
immune system reacts against own Ag
A. Organ speciIic
Hashimoto's thyroiditis
Graves-Basedow disease
chronic atrophic gastritis - pernicious anemia
DM type I.
B. Systemic (multiorgan)
aIIection oI vessels and/or connective tissue,
variable symptomatology
systemic disorders oI connective tissue (collagenosis)
rheumatic Iever
Systemic lupus erythematosus
(SLE)
Iebrile inIlammatory multisystemic disease -
variable symptomatology
Iemales (F:M 0:), 2.-3. decade
most oIten aIIected: skin, kidneys, serosal
membranes, joints, heart
several types oI Ab - namely antinuclear Ab
Iormation oI immuncomplexes
histologically - predominantly necrotizing vasculitis
LE cells (Iagocytosis oI hematoxylin bodies -
destroyed nuclei oI cells) - lab test
Symptomatology
Skin - Iacial exantema (butterIly) - cheeksradix oI the nose
Pleurapericardium - serous and Iibrinous exsudation - Iibrosis
Heart - pericarditis
endocarditis Libman-Sacks (verrucous) - nonbacterial thrombotic
endocarditis
both sides oI the valve
Kidneys - various Iorms oI GlnI
Joints - swelling, inIlammation
Spleen - thickening oI the capsule (serositis)
concentric perivascular Iibrosis (onion-like)
Typical clinical presentation
young Iemale, butterIly-shaped exantema oI the
Iace
Iebrile, joint pain, pleuritic pain, photophobia
ANCA
!!!CAVE!!! Irequently atypical symptomatology
clinical course:
progressive - death
recurrences and remissions - years or decades
treatment: steroids, immunosupression
Rheumatoid arthritis (RA)
symetric chronic inIlammation oI the joints
non-purulent productive synovitis - pannus
(granulation tissue)
destruction oI cartilage - progressive
impairment oI Iunction
rather Irequent: Iemales 0,5-4, males 0,-
,3 (F:M3-5:)
usually young adults
pathogenesis - both humoral and cellular
immunity
increased Ig in serum
"rheumatoid Iactor"
clinically:
symetric inIlammation oI small joints (hands and
Ieet), later also ankle, wrist, elbow, shoulder, jaws
only rarely hips
deIormation and loss oI Iunction oI joints
sometimes Iormation oI subcutaneous nodules (2-
3 cm in diam.) - rheumatoid nodules
Special Iorms oI RA
Juvenile RA (Stils disease) - age -3 y.
RA Iever, hepatosplenomegaly,
lymphadenopathy
Felty's disease
RA splenomegaly leukopenia
Systemic sclerosis (SS)
interstitial tissue oI various organs - inIlammation and
Iibrosis
in 95 skin (scleroderma)
sometimes visceral lesions (GI tract, lungs, kidneys,
heart, muscles) most important
F:M3:
any age (childhood - old age), mainly 3.-5. decade, rare
histologically:
sclerosis oI collagen (loss oI Iilamentous structure,
homogenization, hyalinization, no nuclei)
skin - Iingers - progression proximally
Iirst edema, than sclerosis oI collagen,
atrophy oI epidermis, loss oI skin adnexa
skin is dry, with smooth surIace, shiny, thin
- ulceration
loss oI elasticity, rigidity
spontaneous amputations, mask Iace
GI tract
namely esophagus - atrophy and Iibrosis oI the
wall - problems with swallowing
Locomotory apparatus
loss oI mobility, rigidity
Lungs
interstitial Iibrosis
Heart
interstitial Iibrosis oI myocardium
Vessels
Raynaud's phenomenon - polyarteritis nodosa
Polymyositis (dermatomyositis)
symetrical muscle weakness, pain, swelling,
atrophy
2 peaks oI incidence - 5-5 y., 50-60 y.
Irequently combination with other systemic
diseases - overlap syndromes, vasculitis
mixed connective tissue disease
Polymyositis (dermatomyositis)
Histologically
inIlammation (lymphocytes, plasma cells,
histiocytes)
atrophy, necrosis, disappearance oI muscle Iibres,
replacement by Iibrous tissue and Iat
usually starts proximally (shoulder, pelvis) - distal
progression
in 0-20 combination with malignant tumors -
ca lungs, GIT (males) or ca breast, ovary (Iemales)
Sjgren's syndrome
dry eyes (keratoconjuctivitis sicca) - corneal lesions
dry mouth (xerostomia)
caused by loss oI salivary and lacrimal glands -
immunologicaly induced inIlammation
only salivary glands - benign lymphoepithelial lesion
(myoepithelial sialoadenitis) - see Mikulicz's sy
salivary glands lacrimal glands - sicca syndrome
combination with other autoimmune disorders (RA -
60) - Sjgren's sy - 933
involvement oI glands oI other systems (nose,
pharynx, vagina)
histologically:
lymphoid inIiltrates, atrophy - loss oI parenchyma
mostly Iemales, over 40 y.
Dx. based on histology (excision oI minor salivary
gland)
Mikulicz's syndrome
bilateral swelling oI lacrimal glands, parotis and
submandibular glands
various etiology (leukemia, lymphoma, syphilis,
TBC) cases with unknown etiology - Mikulicz's
disease
Polyarteritis (periarteritis) nodosa
necrotizing inIlammation oI the wall oI middle
sized and small arteries - necrotizing vasculitis
deposition oI immuncomplexes (similar to
Arthus's phenomenon)
oIten segmentally (uninvolved skipped areas) -
thrombosis - inIarctions
variable clinical presentation - most Irequently
kidneys, heart, liver, GIT (perIoration!), lungs
rarely!
Polyarteritis (periarteritis) nodosa
histologically:
Iibrinoid necrosis (eosinophillic),
inIiltration by neutrophillic leucocytes,
microaneurysms - rupture or thrombosis -
inIarction
healing by scar (Iibrous tissue)
M:F2: (!predominance oI males!)
Dx. based on histology - diagnostic excision
egener's granulomatosis
rare
acute necrotizing arteritis (similar to polyarteritis
nod.) - kidneys, respiratory tract (lungs), spleen
acute granulomatous inIlammation, necrotizing -
namely respiratory tract (nose, paranasal sinuses,
larynx, trachea, bronchi, lungs)
necrotizing progressive GlnI. - in the past Iatal,
today cytostatics
3. ImmunodeIiciency diseases
A. Primary immunodeIiciency states
B. Secondary immunodeIiciency states
A. Primary immunodeIiciency
states
experiments oI nature, extremely rare
X-linked agammaglobulinemia (Bruton's disease)
inability oI pre-B cells to diII. into mature B-cells
decrease in circulating B-cells, no germinal centers in
LN, rudimentary Peyer's patches
recurrent bacterial inIections (H. inIlu., Str. pneumon.,
Staph. aur.)
Isolated deIiciency oI IgA
most Irequent (:700)
recurrent sinopulmonary inIections, diarrhea
Thymic hypoplasia (DiGeorge's syndrome)
congenital malIormation oI 3rd and 4th
branchial pouches
vulnerability to viral, Iungal and protozoal
inIections
Severe combined immunodeIiciency
X-linked or autosomal recessive
B. Secondary immunodeIiciency
states
more common
in malnutrition, inIection, cancer, renal
disease, malignancies
patients treated by immunosupressive drugs
AIDS
Acquired immunodeIiciency
syndrome (AIDS)
viral etiology (HIV, RNA retrovirus)
severe immunosupression - opportunistic inIections, secondary
tumors, neurologic symptoms
Iirst recognized 98 - Los Angeles - pneumocystic pneumonia
in 5 young homosexuals - 2 died
Pneumocystis carinii (interstitial pneumonia in premature
inIants)
onset oI epidemic
998 - 33,4 million oI inIected (22,5 in sub-Saharian AIrica)
number oI both inIected and ill patients increases - USA, AIrica
(2/3 oI all cases in the world), Southeast Asia (Thailand, India,
Indonesia)
Transmission
. sexual contact (lymphocytes in semen)
2. parenteral - blood derivates, drug abusers
sharing needles
3. mother-to-inIant - transplacental, intrapartum,
breast-Ieeding
HIV cannot be transmitted by casual personal
contact !!!
No transmission from patient to doctor (and
vice versa) by casual contact !!!
Prevention of injury - needle sticks, etc.;
operation or autopsy - special precautions
Epidemiology - 6 risk groups
. homosexual males (60)
2. intravenous drug abusers (24)
3. hemophiliacs ()
4. other blood recipients (2)
5. heterosexual partners oI other high-risk
groups members
6. children oI parents Irom groups .-3.
HIV- and HIV-2 - closely related
long incubation period
tropism Ior lymphocytes and nervous
system
immunosupression - CD4 T-cells (helpers)
slowly progressive Iatal outcome
Opportunistic inIections in AIDS
protozoal (pneumocystosis-lungs; toxoplasmosis-
lungs or CNS)
Iungal (candidiasis-GIT, respiratory tract;
cryptococcosis-CNS; histoplasmosis-dissem.)
bacterial (mycobacteriosis-Irequently atypical;
nocardiosis-lungs, CNS)
viral (CMV-lungs, GIT, kidneys, CNS; HSV;
varicella-zoster; slow viruses)
Neoplasms in AIDS
Kaposi's sarcoma (sarcoma idiopathicum
hemorrhagicum multiplex) - related to HSV
inIection
non-Hodgkin's ML (Burkitt's or
immunoblastic)
primary ML oI CNS
invasive ca oI uterine cervix
"Typical" patient in the USA
young male homosexual or drug abuser
Iever, weight loss, diarrhea, generalized
lymphadenopathy, multiple opportunistic
inIections, neurologic disorders, secondary
neoplasm(s)
"Classical" clinical course
aIter inIection 4-7 -~ seronegative period -~
seroconversion -~ long latency (2-5 Y) -~
lymphadenopathy -~ AIDS-related complex (ARC
- Iever, weight loss, diarrhea) -~ AIDS
no vaccine, no drugs, only prevention
AIDS - 00 mortality
IV. Amyloidosis
amylum starch; amyloid starchlike
abnormal proteinaceous substance deposited
between cells in many tissues and organs
intercellular pink translucent material
variety oI clinical disorders
A. not a single chemical entity
two major and several minor biochemical
Iorms
several pathogenetically diIIerent
mechanisms
unique tertiary structure - -pleated sheet
conIormation
responsible Ior staining properties and Ior
resistance to enzymes
Chemical nature oI amyloid
two types
immunoglobulin light chains - AL (amyloid
light chain) - in B-cell disorders
nonimmunoglobulin protein - AA (amyloid
associated) - in chronic inIlammations
ClassiIication oI amyloidosis
systemic - kidneys, liver, spleen, adrenals,
lymph nodes
localized - various organs
Systemic amyloidosis
. primary - immunocyte dyscrasias
deposition oI AL-A., produced by aberrant clones oI B-cells -
most Irequent Iorm
A. in multiple myeloma
monoclonal proliIeration (neoplasm) oI plasma cells - monoclonal
gammopathy
multiple osteolytic lesions oI the bones
in addition to monoclonal Ig - production oI isolated kappa or
lambda light chain (Bence-Jones protein)
only 6-5 oI patients with MM develop amyloidosis
other cases oI primary A. - e.g. light chain disease
other B-cell related disorders
2. secondary amyloidosis
reactive AA amyloid - protracted
breakdown oI cells, usually in chronic
inIlammatory disorders
TBC, osteomyelitis, bronchiectasis
RA, connective tissue disorders, ulcerative
colitis, tumors (Hodgkin's ML)
Localized amyloidosis
heterogenous group
nodular deposits - lungs, larynx, skin, urinary
bladder, tongue - inIiltration oI B-cells - probably
well diIIerentiated plasmacytoma
special Iorms:
AE - endocrine tumors (medullary ca oI thyroid)
AS - senile amyloid (brain, heart)
Staining oI amyloid
Gross reactions
Virchow I. - staining by Lugol's sol.
Virchow II. - reaction with H
2
SO
4
Microscopy
metachromasia (cresyl violet, gentian violet)
Congo red - green bireIringence
monoclonal antibodies against diIIerent types oI
amyloid - more precise classiIication
Involvement oI organs
Kidneys
most common, most serious
glomeruli, vessels, peritubular stroma
nephrotic syndrome
Spleen
two types - Iollicular (sago) and diIIuse (lardaceous) spleen
Liver
weight up to 9kg!
space oI Disse - atrophy oI hepatocytes
Heart
AS-amyloid - leIt atrium (ANF granules)
AA - in systemic involvement - Iirm, wax-like
Clinical symptomatology
incidental Iinding at autopsy
severe clinical symptoms - renal
malIunctions, hepatosplenomegaly, heart
involvement
Dx.: needle biopsy oI lesion; in systemic -
biopsy oI rectal or oral mucosa