Immune disorders

immunity & immune disorders - extreme importance (comparable to bacteriology at the early 20th cent.)
new diseases, immunological ethiology in "old" diseases, immunotherapy - considerable amount of medical informations
immune system - important for 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, supressor, killer, natural killer)

Macrophages

Antigen-presenting cells - dendritic cells, Langerhans cells (skin)

MHC system
HLA complex antigens - ability to recognize own Ag from foreign ones
importance in transplantation - rejection (destruction of the graft by host)

1. Immune mechanisms of tissue damage
immune response (both humoral&cellular)
Ag (both exogenous&endogenous)
inappropriate - hypersensitive reaction
allergy - 4 types

I. Anaphylactic type
quickly developing after contact of Ag (alergen) with Ab
previous exposition!
B-cells - IgE
mediated through histamine, leucotriens, prostaglandins (granules of mast cells & basophilic leucocytes)
increase of vascular permeability, vasodilatation, bronchoconstriction, increased mucoproduction

local reaction - skin or mucosa
bee sting, food allergy, hay fever (pollinosis), asthma bronchiale
urticaria (hives)
familiar predisposition - atopy

systemic reaction
parenteral administration of Ag (e.g. antiserum, drug-ATB) - systemic anaphylaxis -> anaphylactic shock
minutes - itching, rush, redding of skin
breathing problems, abdominal pain, vomiting, diarrhea
during several min - death due to collapse of circulation

II. Antibody dependent type
antigens - autologous (own) or homologous (another human)
incompatible blood transfusion - destruction of RBCs
Rh-incompatibility - fetal erythroblastosis (anti-Rh Ab)

III. Immune complex diseases
formation of Ag-Ab complexes (immune complexes)
activation of complement and accumulation of polymorphonuclear leucocytes
acute inflammation of tissues
e.g. serum sickness - repeated exposure to animal (equine) serum (antitetanic)
immunocomplexes are deposited in tissues - inflammation
vessel wall - acute necrotizing vasculitis (fibrinoid necrosis) - thrombosis - ischemic necrosis
vessel wall replaced by smudgy, pink material
local form of IS - Arthus' phenomenon (animal model - skin lesion) - localized area of tissue necrosis resulting from immune complex vasculitis - farmer's lungs (molds on hay)
some types of glomerulonephritis
systemic lupus erythematodes (SLE)

IV. Delayed type of hypersensitivity (tuberculin-type) - cell mediated
cellular immunity - T-cells&histiocytes
frequently granulomatous reaction (epithelioid cells)
TBC, syphilis, leprosy
e.g. tuberculin reaction - Mantoux test
person previously exposed to TBC develops after intradermal injection of Ag skin induration
manifestation after 8-12 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 graft)
hyperacute (Ab mediated) - widespread arteriolitis, arteritis, thrombosis - ischemic necrosis (minutes-hours)
acute (cell mediated) - lymphocytic infiltration, vasculitis, tubulitis, edema (days-months) - biopsy!!! (days-months)
chronic - vascular changes - sclerosis, intimal fibrosis (months-years)

Graft versus host disease (GVHD)
in transplantations of allogenic hematopoietic cells
immunologically competent donor cells transplanted into immunologically compromized recipient
donor's T-cells react against "foreign" recipient's tissues
liver, skin, gut

2. Autoimmune diseases
immune system reacts against own Ag
A. Organ specific
Hashimoto's thyroiditis
Graves-Basedow disease
chronic atrophic gastritis - pernicious anemia
DM type I.

B. Systemic (multiorgan)
affection of vessels and/or connective tissue
variable symptomatology
systemic disorders of connective tissue (collagenosis)
rheumatic fever

Systemic lupus erythematosus (SLE)
febrile inflammatory multisystemic disease - variable symptomatology
females (F:M = 10:1), 2.-3. decade
most often affected: skin, kidneys, serosal membranes, joints, heart
several types of Ab - namely antinuclear Ab
formation of immunocomplexes
histologically - predominantly necrotizing vasculitis 
LE cells (fagocytosis of hematoxylin bodies - destroyed nuclei of cells) - lab test

symptomatology
skin - facial exantema (butterfly) - cheeks+radix of the nose
pleura+pericardium - serous and fibrinous exsudation - fibrosis

Heart
pericarditis
endocarditis Libman-Sacks (verrucous) - nonbacterial thrombotic endocarditis
both sides of the valve

Kidneys
various forms of Glnf

Joints
swelling, inflammation

Spleen
thickening of the capsule (serositis)
concentric perivascular fibrosis (onion-like)

Typical clinical presentation
young female, butterfly-shaped exantema of the face
febrile, joint pain, pleuritic pain, photophobia
ANCA+
!!!CAVE!!! frequently atypical symptomatology
clinical course:
progressive - death
recurrences and remissions - years or decades
treatment: steroids, immunosupression

Rheumatoid arthritis (RA)
symetric chronic inflammation of the joints
non-purulent productive synovitis - pannus (granulation tissue)
destruction of cartilage - progressive impairment of function
rather frequent: females 0,5-4%, males 0,1-1,3% (F:M=3-5:1)
usually young adults

pathogenesis - both humoral and cellular immunity
increased Ig in serum
"rheumatoid factor"
clinically:
symetric inflammation of small joints (hands and feet), later also ankle, wrist, elbow, shoulder, jaws
only rarely hips
deformation and loss of function of joints
sometimes formation of subcutaneous nodules (2-3 cm in diam.) - rheumatoid nodules

Special forms of RA
juvenile RA (Stil disease) - age 1-3 y.
RA + fever, hepatosplenomegaly, lymphadenopathy

Felty's disease
RA + splenomegaly + leukopenia

Systemic sclerosis (SS)
interstitial tissue of various organs - inflammation and fibrosis
in 95% skin (scleroderma)
sometimes visceral lesions (GI tract, lungs, kidneys, heart, muscles) = most important
F:M=3:1
any age (childhood - old age), mainly 3.-5. decade, rare
histologically:
sclerosis of collagen (loss of filamentous structure, homogenization, hyalinization, no nuclei)

skin - fingers - progression proximally
first edema, than sclerosis of collagen, atrophy of epidermis, loss of skin adnexa
skin is dry, with smooth surface, shiny, thin - ulceration
loss of elasticity, rigidity
spontaneous amputations, mask face

GI tract
namely esophagus - atrophy and fibrosis of the wall - problems with swallowing

Locomotory apparatus 
loss of mobility, rigidity

Lungs 
interstitial fibrosis

Heart 
interstitial fibrosis of myocardium

Vessels 
Raynaud's phenomenon - polyarteritis nodosa


Polymyositis (dermatomyositis)
symetrical muscle weakness, pain, swelling, atrophy
2 peaks of incidence - 5-15 y., 50-60 y.
frequently combination with other systemic diseases - overlap syndromes, vasculitis
mixed connective tissue disease
histologically:
inflammation (lymphocytes, plasma cells, histiocytes)
atrophy, necrosis, disappearance of muscle fibres, replacement by fibrous tissue and fat
usually starts proximally (shoulder, pelvis) - distal progression
in 10-20% combination with malignant tumors - ca lungs, GIT (males) or ca breast, ovary (females)

Sjφgren's syndrome
1933
dry eyes (keratoconjuctivitis sicca) - corneal lesions
dry mouth (xerostomia)
caused by loss of salivary and lacrimal glands - immunologicaly induced inflammation
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%) - Sjφgren's sy
involvement of glands of other systems (nose, pharynx, vagina)
histologically:
lymphoid infiltrates, atrophy - loss of parenchyma
mostly females, over 40 y.
Dx. based on histology (excision of minor salivary gland)

Mikulicz's syndrome
bilateral swelling of lacrimal glands, parotis and submandibular glands
various etiology (leukemia, lymphoma, syphilis, TBC) + cases with unknown etiology - Mikulicz's disease


Polyarteritis (periarteritis) nodosa
necrotizing inflammation of the wall of middle sized and small arteries - necrotizing vasculitis
deposition of immunocomplexes (similar to Arthus reaction)
often segmentally (uninvolved skipped areas) - thrombosis - infarctions
variable clinical presentation - most frequently kidneys, heart, liver, GIT (perforation!), lungs rarely!
histologically:
fibrinoid necrosis (eosinophillic), infiltration by neutrophillic leucocytes, microaneurysms - rupture or thrombosis - infarction
healing by scar (fibrous tissue)
M:F=2:1 (!predominance of males!)
Dx. based on histology - diagnostic excision

Wegener's granulomatosis - rare
• acute necrotizing arteritis (similar to polyarteritis nod.) - kidneys, respiratory tract (lungs), spleen
• acute granulomatous inflammation, necrotizing - namely respiratory tract (nose, paranasal sinuses, larynx, trachea, bronchi, lungs)
• necrotizing progressive Glnf. - in the past fatal, today cytostatics

3. Immunodeficiency diseases
A. Primary immunodeficiency states
B. Secondary immunodeficiency states

A. Primary immunodeficiency states
experiments of nature
extremely rare
• X-linked agammaglobulinemia (Bruton's disease)
inability of pre-B cells to differentiate into mature B-cells
decrease in circulating B-cells, no germinal centers in LN, rudimentary Peyer's patches
recurrent bacterial infections (H. influ., Str. pneumon., Staph. aur.)

• Isolated deficiency of IgA
most frequent (1:700)
recurrent sinopulmonary infections, diarrhea

• Thymic hypoplasia (DiGeorge's syndrome)
congenital malformation of 3rd and 4th branchial pouches
vulnerability to viral, fungal and protozoal infections

• Severe combined immunodeficiency
X-linked or autosomal recessive

B. Secondary immunodeficiency states
more common
in malnutrition, infection, cancer, renal disease, malignancies
patients treated by immunosupressive drugs

• Acquired immunodeficiency syndrome (AIDS)
viral etiology (HIV, RNA retrovirus)
severe immunosupression - opportunistic infections, secondary tumors, neurologic symptoms
first recognized 1981 - Los Angeles - pneumocystic pneumonia in 5 young homosexuals - 2 died
Pneumocystis carinii
interstitial pneumonia in premature infants
onset of epidemic
1998 - 33,4 million of infected (22,5 in sub-Saharian Africa)
doplnit podle nejm
number of both infected and ill patients increases - USA, Africa (2/3 of all cases in the world), Southeast Asia (Thailand, India, Indonesia)

transmission:
1. sexual contact (lymphocytes in semen)
2. parenteral - blood + derivates, drug abusers sharing needles
3. mother-to-infant - transplacental, intrapartum, breast-feeding

epidemiology - 5 risk groups:
1. homosexual males (60%)
2. intravenous drug abusers (24%)
3. hemophiliacs (1%)
4. other blood recipients (2%)
5. heterosexual partners of other high-risk groups members
6. children of parents from groups 1.-3.

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

HIV-1 and HIV-2 - closely related
long incubation period
tropism for lymphocytes and nervous system
immunosupression - CD4+ T-cells (helpers)
slowly progressive fatal outcome

Opportunistic infections in AIDS
protozoal (pneumocystosis-lungs; toxoplasmosis-lungs or CNS)
fungal (candidiasis-GIT, respiratory tract; cryptococcosis-CNS; histoplasmosis-dissem.)
bacterial (mycobacteriosis-frequently 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 infection
non-Hodgkin's ML (Burkitt's or immunoblastic)
primary ML of CNS
invasive ca of uterine cervix

"Typical" patient in the USA:
young male homosexual or drug abuser
fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disorders, secondary neoplasm(s)

"Classical" clinical course
after infection 4-7 W -> seronegative period -> seroconversion -> long latency (2-5 Y) -> lymphadenopathy -> AIDS-related complex (ARC - fever, weight loss, diarrhea) -> AIDS
no vaccine, no drugs, only prevention
AIDS - 100% mortality

IV. Amyloidosis
amylum = starch; amyloid = starchlike
abnormal proteinaceous substance deposited between cells in many tissues and organs
intercellular pink translucent material
variety of clinical disorders

A. = not a single chemical entity
two major and several minor biochemical forms
several pathogenetically different mechanisms
unique tertiary structure - ί-pleated sheet conformation
responsible for staining properties and for resistance to enzymes

Chemical nature of A.
two types
• immunoglobulin light chains - AL (amyloid light chain)
in B-cell disorders
• nonimmunoglobulin protein - AA (amyloid associated)
in chronic inflammations

Classification of amyloidosis
• systemic - kidneys, liver, spleen, adrenals, lymph nodes
• localized - various organs

• Systemic amyloidosis
1. primary - immunocyte dyscrasias
deposition of AL-A., produced by aberrant clones of B-cells - most frequent form
A. in multiple myeloma
monoclonal proliferation (neoplasm) of plasma cells - monoclonal gammopathy
multiple osteolytic lesions of the bones
in addition to monoclonal Ig - production of isolated kappa or lambda light chain (Bence-Jones protein)
only 6-15% of patients with MM develop amyloidosis
other cases of primary A. - e.g. light chain disease
other B-cell related disorders

2. secondary amyloidosis
reactive AA amyloid - protracted breakdown of cells, usually in chronic inflammatory 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 - infiltration of B-cells - probably well differentiated plasmacytoma
special forms:
AE - endocrine tumors (medullary ca of thyroid)
AS - senile amyloid (brain, heart)

Staining of amyloid
Gross reactions
Virchow I. - staining by Lugol's sol.
Virchow II. - reaction with H2SO4
Microscopy
metachromasia (cresyl violet, gentian violet)
Congo red - green birefringence
monoclonal antibodies against different types of amyloid - more precise classification

Involvement of organs
• kidney
most common, most serious
glomeruli, vessels, peritubular stroma
nephrotic syndrome
• spleen
two types - follicular (sago) and diffuse (lardaceous) spleen
• liver
weight up to 9kg!
space of Disse - atrophy of hepatocytes
• heart
AS-amyloid - left atrium (ANF granules)
AA - in systemic involvement - firm, wax-like

Clinical symptomatology
incidental finding at autopsy
severe clinical symptoms - renal malfunctions, hepatosplenomegaly, heart involvement
Dx.: needle biopsy of lesion; in systemic - biopsy of rectal or oral mucosa