Download 5 Immunopathology of reproduction

Study materials: Disorders of Immunity, MIIC
1
Repetition - Basic Immunology from MIB and Immunopathology M IIA – see
web materials and textbook: Roitt I, Essential Immunology
2
Immunodeficiency
Pathogenesis of ID, explanation of reasons – gene defects or external events leading to ID. Basic features,
typical laboratory findings
Primary
missing enzyme, missing cell type, nonfunctional component, caused by gene defect.
Severe, prevalent in childhood
Secondary
due to underlying disease - lymphoid malignancy, infection, egg. HIV, malnutrition,
burns, glomerulopathies, loss by GI tract, therapy and events. Any time, usually less severe.
2.1 Primary Immunodeficiency
Antibody deficiency clues from history
Recurrent sinus, chest infections are common (history of repeat ENT surgery), another system is usually
involved, gut infection, meningitis), infection are bacterial and due to common microorganisms (Strepto
pneumoniae, Hemofilus influenzae)
Noninfectious features are common (autoimmune thyroid disease, Immunotrombocytopenic purpura,
artritis), higher risk of tumors.
Designation
Immunoglobulins
Pathogenesis
Inheritance
1. X-linked agammaglobulinemia All isotypes decreased
2. Selective Ig deficiency
IgA def.
Decrease IgA1, IgA2
Mutations in btk
Failure of terminal differentiation
of IgM1 B cells
IgG subcl.def.
Decrease in 1 or more subcl.
Def. of isotype dif.
3. Common variable ID
Decrease in IgG and usually
Unknown
IgA, +- IgM
4. X-Hyper IgM syndrome
Decrease in IgG, IgA,
Mutation in CD40 ligand
IgM usually elevated
5. Transient hypogamaglobulinemia IgG,IgA low
Delayed helper function
in infancy
6. Antibody deficiency with
Normal
Unknown
normal or elevated Ig levels
XL
Variable
Unknown
Variable
XL
Unknown
Unknown
Management of antibody deficiency: Ig replacement therapy, treatment of infection, bone marrow (BM)
or Stem cell (SC) transplantation, gene therapy experimentally
2.2
Combined, dominantly cellular (T cell) immunodeficiency
Clues from history: Present in first few weeks/months of life, infections are often viral or fungal rather
then bacterial, chronic diarrhea is common and often labeled as “gastroenteritis”, respiratory infections
and oral thrush are common, failure to thrive in absence of obvious infections should be investigated
Lymphopenia is present in almost all affected infants
Designation
Ig
Circulating B T cells
Pathogenesis Inheritance
1. T-B+SCID
Decreased
Normal or incr. Low
 chain mutation
Jak 3 mutation
XL
AR
2. T-B- SCID
RAG 1/2 deficiency
Decreased
Normal or incr. Low
AR
Decreased
Low
Low
Decreased
Low
Low
Mutation in
RAG1/2 genes
T, B cells defect AR
from toxic metabolites
Stem cell defect AR
Adenosin deaminase
deficiency
Reticular dysgenesis
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
3. T+B- SCID
Decreased
4. Purine nucleoside
phosphorylase def.
Normal or low
Low
Present
Restricted heterogeneity Missense mutation
in RAG1/2 genes
Normal
Low
T cell defect from toxic metabol.
AR
AR
Management: Antimicrobial therapy, bone marrow, SC transplantation, gene therapy experimental
2.3 Primary cell. mediated ID with other symptoms
DiGeorge anomaly ( ID, hypoparathyroidism, cardiovascular defects), chronic mucocutaneous candidosis,
WA syndrome.
2.4 Primary defects of non-specific immunity
Infections are recurrent and prolonged, clinical features may be minimal despite severe infection
Infections are: poorly responsive to antibiotics, common staphylococcal, involve skin and mucous
membranes, complicated by suppurative lymphadenopathy
Defects of neutrophils – disorder of phagocytosis – Chromic granulomatous disease, LAD syndrome.
Treatment: Antibiotic treatment and prophylaxis, Gamma interferon
2.5 Complement deficiency
Def C1, C2, C4 – Susceptibility to immune-complex diseases
D, B, P
recurrent Neisserial infection
Def C3
Recurrent bacterial infection
C 1 inhibitor deficiency hereditary angioedema
2.6 Secondary immunodeficiency
Secondary causes of immunodeficiency are far more common than primary immunodeficiency.
Decreased synthesis
Increased loss
Malnutrition
Nephrotic syndrome
Lymphoproliferative diseases
Protein-losing enteropathy
Drugs
Burns
Infection (viral infection, chronic infection)
Alcoholism (maternal)
Iradiation
Major surgery
Anesthesia
Some chronic diseases (diabetes)
3
Autoimmunity and Autoimmune diseases
Autoimmunity is an immune response against self antigen or antigens. Autoimmune disease is tissue
damage or disturbed physiological function due to autoimmune response. (Autoimmune response can
occur without disease, caution is required in making the assumption that autoimmune responses
necessarily imply autoimmune disease)
Slight autoimmune reactivity is normal; many self proteins induce an autoimmune response in animals
when injected with an appropriate adjuvant.
3.1 Etiopathogenesis – risk factors
Around 3 % of the population has an autoimmune disease. Many of the major chronic disabling diseases
affecting people have autoimmune diseases.
Rare in childhood, peak between puberty and retirement age, more common in women, prevalence higher
in northern latitudes, higher in westernized industrial societies, clustering within families
Central T-Cell Tolerance
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Peripheral Mechanisms of the Induction of Tolerance. Molecular mimicry - Structural similarity between
self proteins and those from microorganisms may trigger autoimmune response. Once tolerance has
broken down to a particular peptide, the process of inflammation will allow presentation of further
peptides – epitope spreading
The basis for autoimmune disease definition is the knowledge of the autoantigens and
pathophysiology of immune reaction (please recognize autoAg for each autoimmune disease group)
3.2 Antigenic mimicry – example.
Microbial protein
autoantigen
Streptococcal M protein
myocardial myosin
EBV GP110
HLA Dw4
EBV capside antigen
Human IgG
Adenoviral E1B protein
Gliadin protein A
Hepatitis B polymerase
Myelin basic protein
Coxsackie B4 nuclear protein
islet glutamate decarboxylase
Campylobacter jejune glycoproteins
Myelin associated gangliosides and glycolipids
3.3 Genetic factors
.
Multiple genetic factors may cluster within the same family. The genetic contributions to
autoimmune disease almost always involve multiple genes.
Association between HLA and diseases
Spondylartritis deformans
HLA B27
Rheumatoid arthritis
DR4+DR1
Type I DM
DR3+DR4
SLE
DR3
Organ specific autoimmune
DR3 (in association with A1B8DR3 Disease: Addisons, Thyroid,
Pernicious anemia, Myasthenia gravis)
Rare autoimmune diseases are monogenous – AIRE protein defect (central tolerance), FoxP3 defect
(peripheral tolerance).
3.4
Environmental factors on autoimmunity development
Hormones
females are far more likely to be affected than males
Infection molecular mimicry, up- regulation of co-stimulatory molecules
Drugs
will induce pathological immune response-reversible with withdrawal
(immunological response to the drug, mechanism is unknown)
Drug induced autoimmune syndrome
3.5 Treatment of autoimmune disease Replacement of function, particularly endocrinology autoimmune disease, Immunosupression
(lack of specificity, toxic effects!!), biological therapy (MAb). bone marrow transplantation - experimental
3.6 Kidney disease - pathogenic mechanisms
Ab directly react with glomerular, tubular basal membrane, Ag-Ab immunocomplexes are deposited in
kidney or Ag my bind with glomerular BM and react with the antibody
Ab may induce a vasculitis process that damages the capillary plexus of glomerulus
3.7 Autoimmune endocrine diseases
Thyroidal: Thyrotoxicosis, Graves disease
Autoimmune thyroiditis , Hashimoto thyroiditis
Type I DM
Adrenal disease - AI adrenalitis, Addison disease
Gonadal disease
AI polyendocrine syndrome
Type 1 parathyroid, adrenal cortex, gonads, MC candid
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Type 2 adrenal, thyroid, insulitis
Type 3 thyroid, pernicious anemia or DM I, myasthenia
3.8 Autoimmune disease of joints and muscles
Immune mechanisms are responsible for many rheumatology diseases - joint, muscles, or systemic
involvement- „connective tissue diseases“ (CTD)
CTD typically associated with non-organ-specific diseases autoantibodies (AutoAb-typically against
nucleus).
AutoAb are diagnostically useful, not usually responsible for damage
Rheumatoid artritis - Chronic, relapsing systemic inflammatory disease, joint usually involved destructive artritis. Otherwise any organ
Main immunologic features: rheumatoid factors-IgM Ab which binds aggregated IgG , in serum or
synovial fluid. Vasculitis, synovitis, decrease C level
Pathogenesis - probably CD 4+ cells promote macrophages to destroy joints, synovial infiltration by
CD4+ cells, association with DR4, effective therapy against T cells (Cy A), anti TNF alpha, or B cells anti CD20.
Ankylosing spondylitis - spine, SI joints
Reiter disease - artritis, urethritis, conj,-uveitis - T response to sequestrated bacterial antigens
Lupus erythematodes
Blotchy erythema on the dorsum of the hands in a patient with SLE. Not all patients with SLE have the
classical photosensitive 'butterfly' rash.
Well-demarcated digital ischemia due to Raynaud's phenomenon
Systemic lupus erythematodes defin. -Multisystemic inflammatory disease, characterized by antinuclear
antibodies.
ACR criteria (at least 4)
malar, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, serositis, renal involvement
(proteinuria, casts), neurological disorder (seizures/psychosis), hematological symptoms, ANA, anti dsDNA, anti-ENA, antiphospholipid antibodies
Immunopatogenesis SLE - Immunopathologic reaction type II. and III. Deposition of complex dsDNA –
antiDNA. Deposition of Ig and complement - inflammations and tissue damage
Anti-erythrocyte Ab, anti-platelet Ab, coagulation factors Ab - direct pathogenic role
Etiology of SLE – unknown, some hypothesis: Complement deficiency. Classical pathway defect (C1,
C4, and C3) is a risk factor. Secondary deficiency by consumption maintains the inflammation.
Autoantibody production directed against nuclear molecules involved in transcription and translation.
Infection induced? Polyclonal B activation. Defective apoptosis (no FAS defect). Drugs (slow
acethylators) - hydralazin, prokainamid, INH. UV light - apoptosis induction on keratinocytes, Ro, La Ag
expression
Hormones - estrogens accelerate the disease?
Other connective tissue disease
Mixed connective tissue disease (MCTD) - artritis, polymyositis, lung fibrosis, skin, anti RNP. Sjogren
syndrome - autoimmune destruction of exocrine glands. Systemic sclerosis, scleroderma- diffuse sclerosis
of skin, GIT, heart, muscle. Vasculitis - polyarteritis nodosa - multiple aneurysm Polymyositis
primary idiopathic PM/DM, with malignancy, juvenile DM, with other AI disease
Anticardiolipin syndrome (ACS) – recurrent thrombotic vessel occlusions, coagulation disorders,
thrombocytopenia. Primary, secondary, synthesis of Ab against phospholipids with cofactor beta2GPI is
typical.
3.9
Cardiovascular autoimmune diseases
- acute rheumatoid fever – example of AI heart disease induced by Ab crossreactivity between
Streptococus antigens and myocardial proteins.
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
3.10 Vasculitis syndrome
Classification according to vessel size, immunohistochemistry. Vessel wall inflammation leads to
occlusion or aneurysma, rupture. Frequently ischemia is the principle of symptoms. Classification
Polyartrteritis nodosa – 7 % of all vasculitis. Systemic inflammatory disease, aorta and main branches
are usually not involved.
ANCA associated vasculitis – Wegener granulomatosis, microscopic polyangitis. Role PMN in
pathogenesis, role of ANCA on Ly activation
3.11 Neuroimmunology
Multiple sclerosis – probable AutoAg is myelin basic protein, inducing T cell response. Antibody
response against cytosceletal proteins is present.
Myasthenia gravis – Ab against ACH receptors
Autoimmune inflammatory neuropathy – anti MAG, ganglioside, sulfatides
3.12 Bullous skin disease
Pemphigus
Most patients have circulatinganti-desmosomal Ab (desmoglein 3), amount correlate with disease activity
Plasmapheresis reduce Ab titer and disease activity. Similar lesion can be induced in animals by patients
serum IgG from pemphigoid serum in the culture will cause epithelial cell detachment
Direct immunofluorescence is diagnostic- IgG, C3 react with keratinocytes
Treatments - systemic corticosteroids
Bullous pemphigoid
Dermatitis herpetiformis Duhring-itchy, small vesicles. Induced by immune response to food antigens,
similar pathogenesis to CD.
Systemic sclerosis
Cryoglobulinemia - Ig which form precipitates, gels or crystals in the cold
Type I - monoclonal IgM
Type II - mixed type, IgM against Fc IgG
Type III - mixed polyclonal
Cutaneous vasculitis - circulating IK, or ANCA
Hereditary angioedema – inborn defect of C1 inactivator
Urticarial vasculitis
Urticaria - marked wheals with surrounding erythema
3.13 Autoimmune eye diseases
Stevens-Johnson sy - severe form of erythema multiforme - IC - drugs, microorganisms
Uveitis - anterior uveitis, posterior uveitis, lens-induced uveitis
3.14 Autoimmune chest diseases
Granulomatous diseases - TBC, sarcoidosis - multisystem granulomat. disorder
Interstitial lung diseases - Fibrosing alveolitis - cryptogenic f. alveolitis, Pulmonary eosinophilia
Hypersenzitivity pneumonitis (Farmers lungs) - vasculitis – ID diseases induced by Microorganisms
inhalation – IC, lymphocyte infiltration
Vasculitis - M. Wegener, Goodpasture´ syndrom
Allergic Bronchopulmonary Aspergillosis
3.15 GIT and liver disease
Atrophic gastritis and pernicious anemia (APCA)
Gluten enteropathy, celiac disease (CD) – Ab and T cell mediated response to gluten and antigens of gut
enterocytes – (transglutaminase, calreticulin)
IBD - ulcerative colitis,Crohn disease
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Hepatitis - infection - A, B, C
autoimmune - Type I - ANA, ASMA
Type II LKM (IIa), with virus hepatitis C (IIb)
Type III SLA
Primary biliary cirrhosis – antimitochondrial antibodies (against M2 pyruvatdehydrogenase) highly
diagnostic and prognostic
4
Allergy and Anaphylaxis
Atopy – inherited tendency for hyperproduction of IgE antibodies to common environmental allergens.
(about 80 % of atopic individuals have a family history of “allergy”¨), usually with typical clinical picture.
The prevalence of allergic diseases is increasing
Risk factors for allergic diseases –
Atopy
Age – commoner in children than adults
Gender – commoner in boys than girls
Family size – less common in large families
Smoking. high levels of antigen exposure
Dietary factors – good intrauterine nutrition
Type I hypersensitivity – most of the reactions are IgE mediated – IgE mediated release of preformed,
newly generated mediators from mastocytes and basophils
Immediate reactions – wheal-flare reaction in 15-20 minutes, mucosal or systemic reaction
(parenteral – reaction to insect venom, drugs). Direct activation of mast cells – aspirin, tartrazine,
myorelacants, opioides, activation via complement split products C3a, C5a)
Late-phase response – 4-6 h after exposure, lasting for 24 hours. (accumulation of activated
inflammatory cells - eosinophils and T cells)
4.1 Anaphylaxis
Acute, severe, multisystemic potentially lifethreating allergic reaction - generalized degranulation of
sensitized mast cells and basophils after antigen exposure. Clinically – sudden, generalized, dominantly
cardiovascular reaction (collapse) and/or bronchospasm, usually with other systems involved
The most common causes of anaphylaxis – food, bee and wasp venom, drugs, latex rubber
Anaphylactoid reaction – (anaphylaxis-like reaction) is not mediated by IgE antibodies. Prior
sensitization is not needed. Pharmacological mediators – histamine, direct mast cells activators, drugs
4.2 Allergic conjunctivitis – seasonal (hay fever) and perennial. Vernal conjunctivitis – perennial, self
limiting conjunctivitis, with giant papillae on the upper tarsal conjunctiva.
4.3 Allergic rhinitis
The most common allergic disease – seasonal, perennial (pollen, animals, mites, molds as sources of
allergens – characteristics, biological and immunology similarity)
4.4
Bronchial Asthma
Pathophysiology: Generalized, reversible airway obstruction
Bronchial hyperresposiveness
Airway inflammation
Asthma is simple to treat, difficult to manage, impossible to cure.
Precipitating specific factors in asthma - Seasonal tree, grass, weed pollen
Perennial – hose dust mites, animal danders, feathers, fungal spores,
occupational allergens – metals
Non – specific factors
Infections, Irritants – smoking, fumes, Diesel exhaust particles, sulphur
dioxide, some ingested foods and preservatives
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Airway cooling – exercise, cold air temperature
Causes of eosinophilic infiltration in chronic allergen exposure:
Upregulation of VCAM enabling eosinophil recruitment
Maturation and increased survival mediated by IL-3, IL-5 and GM-CSF
Selective eosinophil migration induced by IL-8 and RANTES
Pathological changes of asthma -epithelial cell shedding, subepithelial fibrosis, mucosal edema, smooth
muscle hypertrophy and hyperplasia, thickening of the basement membrane, Eo and mononuclear
infiltration in the mucosa
4.5 Food allergy and intolerance
Principles of intolerance:
Food fad
Psychological aversion
Food intolerance (mechanism unknown)
Food allergy - immune
Food idiosyncrasy (nonimmunological mechanism) – irritants, pharmacological,
metabolic effects, enzyme deficiency.
IgE reaction – Food allergens Type I – capable to induced sensitization. Type II, structurally similar to
other inhalation allergens
Components in food – traces of antibiotics, food additives (monosodium glutamate), coloring agents,
preservatives
Clinical syndromes – GI symptoms, acute angioedema, urticaria, perioral erythema (children), atopic
eczema, bronchospasm, hypotension
“Non IgE reactions” T cell reactivity probable, Eo involvement.
Diagnosis of food allergy – history, eliminations and challenge diet form the basis of the diagnosis of food
allergy. Skin test and IgE testing is not usually reliable
4.6 Drug allergy
Minor part of drug side effects have immune mechanisms, all type (I – IV) of hypersensitivity are
involved.
Younger age, women, genetic factors, chemical structure of drug, previous exposition, application are risk
factor for allergy.
Common triggers – penicillin ATB, nonsteroidal anti-inflammatory, general anesthesia drugs, Radio
contrast media, vaccines, latex (show immunopathologic reactions)
4.7 Urticaria and angioedema
Urticaria refers to transient episodes of demarcated, edematous, erythematous, pruritic lesions with a
raised edge.
Clinical diagnosis is easy, finding the cause is very difficult
Angioedema is a similar process occurring in the deep dermis, subcutaneous tissue or mucous membranes.
U and A commonly coexist.
Mechanisms of urticaria production - Immune mechanisms
IgE, complement. Autoimmune (?) FcRI
antibodies
Direct action on mast cells – Aspirin, NSAID, ACE inhibitors, opioids, azo dyes
Acute urtica versus chronic urtica (more than 6 weeks)
Physical urticaria – itching and wheals are provoked by physical stimuli (stroking, cold, sun, water,
exercise, heat)
Urticarial vasculitis – immune complex disease, histological evidence of vasculitis
Clinical identification wheals are usually tender, painful rather than itchy
Generally last longer than 24 hours
Wheals fade to leave purpura or bruising
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Often accompanied by systemic features such as fever artralgie, patients
may have underlying disease (SLE)
4.8 Atopic eczema
Common, chronic, severely pruritic, eczematous skin disease, usually in individuals with a hereditary
predisposition to atopic disorders
Prevalence
children under the age of 2 years – 10 %
Adults 2 %
Complication – bacterial superinfection
Diagnosis – on the basis of clinical features
Immunologic abnormality:
Raised serum total IgE in about 90 % of patients. Abnormal T cell function – increased
susceptibility to skin infection, normally controlled by T cells (vaccinia, herpes simplex, viral warts)
Impaired delayed hypersensitivity skin test response. Decrease number of Th1 cells, expansion of Th2
cells, chronic macrophage activation. Food allergy common in childhood, rare in adulthood.
4.9 Contact dermatitis
Inflammatory skin disease caused by T-cell mediated hypersensitivity to external agents – dominantly
occupational disease
Agents responsible for contact dermatitis
Metals
nickel, chromate (cement), cobalt
Medication
“para” -group chemicals – anesthetics, sulphonamide antibiotics, PABA
containing substances, Phenothiazines, neomycin
Plastics
acrylates
Rubber
accelerators
Plants
Primula, Poison Ivy, chrysanthemum
Cosmetics
Perfumes, preservatives, lanolin
5
Immunopathology of reproduction
Immunity related to –conception, nidation , intrauterine tolerance, response to sperm antigens (men,
women), mother immune response during pregnancy, sterility and infertility
Survival of fetus as a allograft - hemochorial placenta - syntitiotrofoblast - no HLA Class I but class G
expression, fetal antigens expressed weakly. Uterus is not a privileged site, mild exchange of soluble
factors and cells between the mother and the fetus (200 000 cells / day). Placental immunoglobulin
crossing - only IgG immunoglobulin. autonomous IgM, IgA production (infection)
crossing Ab in case of incompatibility A,B,O or Rh = HDN
crossing of autoantibodies - mother AI disease
Maternal immune response during pregnancy- Decreased number of lymphocytes, decrease of CD4
cells, increase of CD8 cells, decreased proliferate response of T lymphocytes, Increased Ig concentration
Immune reaction after repeated abortions - Negative influence of the same HLA antigens - therapy:
immunization of mother by father antigens.
Antiphospholipid antibodies, Autoimmunity to trophoblast, endometrium, Autoimmunity of thyroidal AI
Immune response to sperms - Man = autoimmunity, women = alloimmunity
6
Transplantation immunology
6.1 ALLOIMMUNITY AS AN INFLAMMATORY RESPONSE
In patients who are serologically presensitized to alloantigens (ie, graft antigens recognized as "non-self"),
this can rapidly proceed to a pathologic thrombotic response (hyperacute rejection).
When graft alloantigens are encountered by T cells, the inflammatory responses intensify, and pathologic
tissue destruction ensues (acute rejection).
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
When these T-cell-dependent responses to graft alloantigens are controlled by immunosuppressive drugs,
acute rejection is avoided, but tissue repair mechanisms are allowed to engage.
If the repair and structural reinforcement process is prolonged, pathologic tissue remodeling occurs
(chronic rejection).
Mechanisms of tissue damage
antigen-independent causes of tissue damage associated with allograft transplantation, including
peritransplant ischemia, mechanical trauma, and reperfusion injury
antigen-dependent causes, such as immune-mediated damage to graft tissues. Any tissue damage
in the graft compromises graft acceptance by promoting graft inflammation, a complicated array of events
that promotes control, pathogen surveillance/eradication, and tissue repair.
6.2 Pathways for the presentation of alloantigenic peptides
1. Proteins derived from graft cells are obtained by recipient antigen-presenting cells
(APCs), processed, and displayed via recipient major histocompatibility complex (MHC) class II
molecules to recipient CD4+ T cells.
2. Proteins produced by graft-derived antigen-presenting cells (APCs) are processed and displayed
via graft-associated major histocompatibility complex (MHC) class I molecules to the recipient CD8+ T
cells.
3. Proteins produced by graft-derived antigen-presenting cells (APCs) are processed and displayed
via graft-associated major histocompatibility complex (MHC) class I molecules to the recipient CD8+ T
cells.
6.3 TYPES OF GRAFT REJECTION
Hyperacute rejection
Presence of large numbers of polymorphonuclear leukocytes. Occurs within minutes to hours of graft
implantation. Dependent on the presence within the graft recipient of preformed circulating antibodies
with specificities for foreign protein polymorphisms displayed by the graft endothelia (ABO, MHC
encoded proteins) . 1 %. Avoidance of high-risk donor-recipient combinations
Acute Rejection
Acute rejection is characterized by the presence of leukocytes - macrophages and T cells
Within the interstitial infiltrate of acutely rejecting grafts is a small number of recipient-derived, donor
alloantigen-reactive T cells, on which the process of acute rejection is absolutely dependent
50 % . Immunosuppressive drugs
Chronic Rejection
Development of blood vessel luminal occlusion due to progressive neointimal formation within the large
to medium arteries and, to a lesser extent, veins of the graft. It represents a pathologic tissue-remodeling
response. 10-year graft survival can be reliably evaluated, chronic graft rejection occurs in about 50% of
transplant patients. Currents IS have little effect
Transplantation History
First kidney transplantation - 1954
First heart transplantation 1967
First bone marrow transplantation - 1968
6.4 Selection of donor/recipient for kidney
Living relative - two kidneys, no transmissible disease, no anomalous blood vessels, good psychologically
health
Cadaver - good renal function, no infection, malignancy, systemic disease
Recipient selection
ABO compatible, negative serum cross match (T ly), HLA match, particularly D loci
6.5 Pre - transplantation testing
Blood group - A,B,O, HLA antigens Class I and II . Mixed lymphocyte culture - MLR , Cross - match
Alloreactivitiy testing of T cells - mixture of donor and host lymphocytes - positive result - lymphocytes
lysis
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Immunologically privileged sites (gonads, cornea) No rejection in allogenic transplantation
Stem cell transplantation - indication
Severe aplastic anemia, Acute/chronic myeloid leukemia-1rst remission, acute lymphoblast leukemia
Immunodeficiency - SCID, CGD, WA, hyper IgM - severe cases. Inborn errors of metabolism
Autoimmune diseases - peripheral SC
6.6 Graft versus host disease
It occurs in most patients with allogenic transplants. Presence of immunocompetent T cells in graft
HLA incompatibility between donor and recipient, cellular immune deficiency in the host
Clinical picture - Rash, fever, hepatosplenomegaly, bloody diarrhea, breathlessness,
7 - 14 days after transplantation
Prevention - Irradiated blood products in immunosupressed hosts ( T cells inactivation), T cells depletion
7
Immunohematology and lymphoproliferation
7.1 Immune reactions against blood elements
Two classes of antibodies, IgG and IgM, are each associated with distinctive serologic reactions and
different clinical forms of immune hemolytic anemia. Similarly, thrombocytopenia, neutropenia, against
soluble clotting factors, ("lupus anticoagulant"/ antiphospholipid antibody (APA) syndrome.
Direct antiglobulin test (DAT) uses the patient's own cells as the targets for the Coombs reagent; a
positive test result indicates the presence of antibodies or complement directly on the patient's cells.
However, the frequency of positive test results in hospitalized patients may run as high as 15%.
Mechanisms of autoimmune hemolytic anemia
Warm reactive IgG autoantibodies, best detected at 37 ° C
Cold reactive IgM autoantibodies, detected at the temperature bellow 37 ° C
Drug provoked immune hemolytic anemias
Complement activating IgG of paroxysmal cold hemoglobinuria
Classification of AIHA
warm (IgG)
primary
secondary
lymphoproliferation, autoimmune disease, AIHA
drugs, infection
cold (IgM)
primary
secondary – infection, lymphoproliferation, paroxysmal cold
hemoglobinuria,
7.2 Warm autoimmune hemolytic anemia
Clearance of IgG-coated red blood cells (RBCs). Removal is mediated by attachment to Fcgamma
receptors located predominantly in the spleen. Red blood cells that survive this process partially
phagocytized become spherocytes, a characteristic morphologic feature of immune hemolysis. The IgGcoated cells undergo accelerated destruction by attachment to Fc receptors present on macrophages of the
RES, primarily those located in the spleen
7.3 Cold Agglutinin Hemolytic Anemia
Cold-reactive IgM autoantibodies fix early complement components to the red blood cell membrane.
Rewarming results in additional activation of the complement system, leading to extravascular removal (
hepatic RES cell C3 receptor binding) or intravascular destruction. Cold agglutinin disorders are
subdivided into primary (idiopathic) and secondary forms; the idiopathic form can be considered to be a
form of paraproteinemia with an IgM monoclonal autoantibody. The mechanism of hemolysis that results
from the presence of cold agglutinins differs significantly from WAIHA.
Paroxysmal cold hemoglobinuria is the rarest form of an autoimmune hemolytic disease. It results from
a cold-reacting IgG antibody (the Donath-Landsteiner antibody), usually with specificity for a universal
RBC determinant, the P antigen. The antibody fixes early complement components to the cell; on
rewarming, the remainder of the complement sequence is activated, leading to intravascular lysis
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
7.4 Drug-Induced Hemolysis
A large number of drugs are capable of causing immune hemolytic reactions in susceptible individuals
(1) the drug adsorption type
(2) the immune complex type
(3) the autoantibody type
Penicillin is the prototypical example of the drug adsorption mechanism (very high doses - 10 - 20 million
7.5 Hemolytic disease of the newborn
consequence of the binding of maternal alloantibodies or isoantibodies to the inherited paternal antigens
present on fetal RBCs, which the mother lacks. The commonest cause - rhesus incompatibility Rh Dwomen are at risk
Prevention - anti - D antibody after delivery in the first pregnancy (destroy Rh+ fetal cells)
7.6 Hemolytic Transfusion Reactions
The most common cause of AHTR - the transfusion of ABO-incompatible RBCs because of a clerical
error
Delayed hemolytic transfusion reactions - a result of an anamnestic response from exposure to minor
RBC antigens, typically those belonging to the Rh, Kell, Kidd, or Duffy blood groups
7.7 Immune Thrombocytopenia
Immune mechanisms similar to those described for RBCs can also cause thrombocytopenia
The major diagnostic criteria are : (1) a low platelet count
(2) evidence for a destructive cause of the thrombocytopenia (eg, large platelets in the peripheral
blood, a bone marrow that shows normal to increased numbers of megakaryocytes)
(3) the absence of other causes of a destructive thrombocytopenia.
7.8 Immune Neutropenia
Neonatal alloimmune neutropenia (transient congenital neutropenia) occurs when maternal neutrophilspecific antibodies cross the placenta.. Drug induced neutropenia. Secondary neutropenia - SLE
7.9 ANTIBODIES AGAINST CLOTTING FACTORS
The antibody is directed against a specific clotting factor, such as factor VIII antibodies (15 % of patients
with severe hemophilia, the antibody act as a nonspecific blocking factor (prothrombin converter complex
- the lupus anticoagulant/APA - different antibodies, related pathogenesis of AP syndrome)
Lupus Anticoagulant/APA Syndrome
The lupus anticoagulant is an IgG or IgM antibody that prolongs clotting tests by binding to anionic
phospholipids that have formed complexes with proteins. Lupus anticoagulants are one of the most
common coagulation abnormalities seen in clinical medicine and have been associated with thrombosis
and recurrent fetal loss
7.10 IMMUNOHEMATOLOGIC ASPECTS OF B-CELL DISORDERS
Clonal neoplasms, such as CLL, macroglobulinemia of Waldenstrom, and multiple myeloma, can be
considered to represent a maturation arrest in the normal sequence of the cellular responses of B
lymphocytes to antigenic stimulation.
B lymphoproliferative disease Chronic lymphocyte Leukemia, Monoclonal Gammopathies, Macroglobulinemia of Waldenstrom,
Amyloidosis - the extracellular tissue deposition of an insoluble fibrillar protein
Cryoglobulinemia - proteins that precipitate when exposed to cold and redissolve with rewarming
8
8.1
Tumor immunology
MECHANISMS OF ESCAPE OF TUMOR CELLS FROM THE IMMUNE SYSTEM
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Downregulation of MHC Class I expression, Lack of costimulatory function. Immunoselection of tumor
cells with weak immunogenicity. Tolerance of the host to respond to tumor antigens. Suppression of
immune response by tumor secreted products. Induction of regulatory/suppressor cells
8.2 Tumor immunotherapy:
active immunization – cytokine use – IL-2, dendritic cells pulsing by tumor antigens – specific T
cell induction
passive – targeted drug by tumor Ag specific Ab (MAb), directed polymers. Monoclonals against
vascular growth factors, specific cell (tumor) Ag – rituximab anti CD20 etc. Activated killer cells.
9
Immunomodulation and immunotherapy
Goals of immunotherapy
Immunostimulation
specific - immunization against infection
nonspecific - synthetic stimulators, bacterial lysates, derivates
Immunosuppression
nonspecific - synthetic drugs, cytokine intervention (AI, transplantation, severe
allergy)
specific - allergy, AI diseases (research)
9.1 Vaccination against infectious diseases
Active immunization
natural infection (survived)
artificial-mimic the immunological stimulus
Passive immunization
natural
artificial
Ideal vaccine: effective, safe, cheap, ready available, stable, easy administered, with long last effect
Vaccination against infectious diseases-immunization
Immunization is undergoing important changes, with improved vaccines replacing less immunogenic or
less safe vaccines, new vaccines for common diseases.
Immunological requirements of a vaccine
Activation of APC to initiate antigen processing and production of cytokines
Activation of both T and B cells to give a high yield of memory cells
Generation of T cells to several epitopes to overcome:
antigenic variation of pathogens
genetic variability in the host´s immune response due to MHC polymorphism
Persistence of antigen on follicular dendritic cells in lymphoid tissue where memory B cells are recruited.
Live attenuated vaccines fulfill these criteria par excellence
9.2 Vaccines
Live vaccines - infect, replicate, and immunize, without causing significant disease (BCG, Polio-Sabin,
MMR) Not a fully virulent organism - attenuated - !!Risk for ID!!
Killed vaccine - suspension of killed organisms (cholera) or products or fractions (pertussis). Toxoids
(tetanus), subunits of viruses (split vaccines)
Adjuvants - enhance the immune response to another antigen given simultaneously - Freund´s,
aluminium, muramyl dipeptid, polymers
9.3 Nonspecific stimulation Synthetic levamisol
isoprinosine
Bacterial immunomodulators
Products of immune system - transfer factor , thyme hormones, cytokines
9.4
Immunosuppressive therapy AI disease, transplantation
Corticosteroids
IS targeted to DNA metabolism
Antagonists and inhibitors of nucleotides - azathioprin, mycofenolic acid, cyklofosfamid,
antimetabolites
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera
Study materials: Disorders of Immunity, MIIC
Molecular effects of glucocorticosteroids
Immunosuppressive therapy - corticosteroids
Immunosuppressive therapy - selective for immune cells
IS antibiotics - molds products, bound to cytoplasmic immunophillins - transcription inhibition for
gee for IL-2 - cyclosporine A, FK506 (tacrolimus), rapamycin
Antibodies to T cells antilymphocyte serum, antithymocyte serum, anti CD3
Interferons - Antitumor effect, antiprolipherative effect, increase antigenicity of tumor cells, NK activity
stimulation, Immunomodulatory effect -Macrofages activation, MHC induction.
Antiviral activity
(IFN-alpha). Side effect - vascular leak syndrome
Mechanisms of Action of Intravenous Immunoglobulin (IVIG). Chimeric, humanized antibodies
Immunosuppression by antigen - Tolerance induction by oral antigen. Limited by the knowledge of the
autoantigen, probably tissue specific still experiments
9.5 Therapy of atopic diseases – allergy vaccination/allergen immunotherapy
causal therapy of atopic diseases. – inducing clinical tolerance to causal allergen. Immune changes increased T regulatory activity, suppressive cytokine production IL-10), reduced mast cells, basophil
activity, decrease eosinophil tissue recruitment and activation
Parenteral, or sublingual application (negative signals induction from mucosal dendritic cells)
9.6 Use of cytokines, cytokine antagonists membrane antigens
Neutralizing of IL-4 anti-IL-4 prevent development of all.Sp.IgE, reduce IL-5, eosinophilia, airway
hyperreactivity. Soluble cytokine receptor represent endogenous homeostatic mechanism, at high dose can
block IL function a modify the disease
Proinflammatory cytokines inhibition- IL-1Ra (rheumatoid artritis), anti TNF
9.7 Monoclonal Ab as Immunosuppression
Anti CD3
renal, heart graft rejection
Anti TNF.-alpha – rheumatoid arthritis, M.Crohn – disease modification
anti-CD20 (rituximab) chimeric antibody - human Fc part combined with mouse variable domains –
CD20 expressing lymphoma, rheumatoid artritis, IBD
anti-integrin (natalizumab) – multiple sclerosis
anti-IgE (omalizumab) asthma, allergy
anti-VEGF, EDGF (growth factors) – solid tumors therapy
9.8 Gene therapy for immunodeficiency diseases
Gene therapy is the process by which exogenous genetic material is transferred into somatic cells to
correct an inherited or acquired gene defect or to introduce a new function or property into cells.
The first human protocol for gene therapy was performed in patients with ADA (T cell ID) deficiency in
1990 at the National Institutes of Health
Recommended literature:
Medical Immunology. Parslow TG, Stites DP, Terr AI,. - 10th ed. - London: Mc Graw-Hill, 2001.
Essentials of Clinical Immunology, Chapel H, Haeney M et al. Blackwell Science, 5th ed. 2006
Primer on Allergic and Immunologic Diseases , Shearer WT, Li JT, J Allergy Clinical Immunology. 2003,
111, 2, Supplement.
Dept. Immunology, 3rd Medical Faculty, Charles Univ
Doc. Kučera