IgG and IgM based immunopathological reaction
(reaction of hypersensitivity type II).
•= antibody-dependent
 antibodies produced by the
immune response bind to
antigens on the patient's
own cell surfaces
 intrinsic ("self" antigen,
innately part of the
patient's cells)
 extrinsic (absorbed onto
the cells during exposure
to some foreign antigen,
possibly as part of infection
with a pathogen)
 These cells are recognized by macrophages or dendritic cells which act as
antigen presenting cells, this causes a B cell response where antibodies are
produced against the foreign antigen.
IgG and IgM based immunopathological reaction
(reaction of hypersensitivity type II)

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
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Autoimmune hemolytic anemia
Goodpasture's syndrome
Autoimmune pernicious anemia
Immune thrombocytopenia
Transfusion reactions
Myasthenia gravis
Rheumatic fever
Acute transplant rejection
Immune complex based immunopathological
reaction (reaction of hypersensitivity type III)
 occurs when antigens and antibodies are
present in roughly equal amounts, causing
extensive cross-linking
 large immune complexes that cannot be cleared
are deposited in vessel walls and induce an
inflammatory response
 the reaction can take hours, days, or even
weeks to develop
Immune complex based immunopathological
reaction (reaction of hypersensitivity type III)
Some clinical examples:
Rheumatoid arthritis
Immune complex glomerulonephritis
Serum sickness
Subacute bacterial endocarditis
Systemic lupus erythematosus
Farmer's lung (Arthus-type reaction)
Polyarteritis nodosa
PRIMARY
IMMUNODEFICIENCY
 clinical manifestactions
 examples
IMMUNODEFICIENCY
 Primary immunodeficiencies
- congenital, genetically defined disorders
- onset of symptoms - predominantly at an early
age
 Secondary immunodeficiencies
- caused by chronic infections, irradiation,
injuries, immunosupression therapy, surgery,
stress
- disorders appear at any age
IMMUNIDEFICIENCY
 Humoral deficiency disorders
= the B cell deficiency disorders – the qualitative or
quantitative defects of the B cells, present 70% of IDs
 T cell deficiency disorders and the combined B-cell
and T-cell deficiency disorders (20%) – group of the
qualitative or quantitative defects of the T and B cells
 Phagocytic cell disorders– group of the qualitative or
quantitative defects of the fagocytic cells (10%)
 Complement disorders – caused by the deficiency of
the complement components or functions (<1%)
MAJOR CLINICAL FEATURES
 Humoral deficiency disorders - manifest as the recurrent bacterial
sinopulmonary and gastrointestinal infections
- caused by streptococcus, staphylococcus, haemophilus, begin
when infants are 5-9 months of age
 T cell disorders - manifest as the recurrent bacterial, fungal and
viral respiratory and gastrointestinal infection
 Complement disorders – are associated with increased incidence
of the infections and autoimmune diseases and with edema in the
case of hereditary angioedema
 Phagocytic cell disorders – characterized by recurrent infections
caused by various organisms incluging abscesses, purulent skin
infections, granulomatous inflammations
HUMORAL DEFICIENCY DISORDERS
Bruton’s X-linked hypogamaglobulinemia
CVID - Common Variable
ImmunoDeficiency
Selective immunoglobulin A deficiency
<0,07 g/l
Bruton’s X-linked
hypogamaglobulinemia
 the genetic defect on the X chromosome leads to the defective
function of a tyrosine kinase in the B cells
 This defect result in a block of the pre-B cells maturation into the B
cells with surface IgM
 the immunologic findings: < 2% circulating B cells
- low serum levels of all classes of immunoglobulins
- number and function of T cells are intact
- pre-B cells are in the bone marrow
 features : begining from 5-9 months of age
- manifests as recurrent bacterial sinopulmonary and gastrointestinal
infection caused by streptococcus, staphylococcus, haemophilus,
meningococcus, salmonella, campylobacter, giardia
 Treatment consists of life-long intravenous pooled human
gammaglobulin replacement and antibiotics.
Common Variable ImmunoDeficiency
 the B cell functional disorder characterized by the normal number
of the B cells, low levels of IgG and IgA, a poor response to all
vaccines and decrease of the T cells (CD4+) number and function
 the symptom’s onset between 2nd and 3rd decade
 the clinical features:
- recurrent respiratory tract infections (pneumonia), cutaneous and
gastrointestinal infection
- disease is accompanied by occurrence of the granulomas,
lymphadenopathy, splenomegaly
 Treatment consist of the intramuscular or intravenous
gammaglobulin replacement.
Selective deficiency of IgA
 level of IgA up to 0,05 g/l, age > 4 years
 the most frequent primary ID
- stem cell defect
- repeated infections of respiratory tract
- susceptibility to autoimmune disorders,
malignant disorders, allergy
- contra-indication of administration of drug with
IgA
T cell deficiency disorders
 DiGeorge syndrome
- the genetic defect on the chromosome 22 leads to disorder of
development of 3rd and 4th branchial pouch with congenital
hypoplasia of both the thymus and parathyroid glands
- patients suffer from disorder of pre-thymocytes maturation due to
absence/hypoplasia of thymus
- syndrome CATCH 22: cardiac defects, abnormal facies, thymic
hypo/aplasia, cleft palate, hypocalcemia, deletion 22q11.2
- the symptom’s onset soon after the birth – hypocalcemic spasms
and manifestations of congenital heart disease
- treatment: symptomatic, transplantation of a thymus
PRIMARY FAGOCYTIC CELL DEFECTS
Chronic granulomatous disease
- X- linked recesive disorder - leads to defect in neutrophilic
cytochrome b with suppresion of intracellular killing of ingested
microorganisms
- normal number of leucocytes
- infection of catalase-positive bacterias
- symptoms appear in the first year of age: pyogenic cutaneous
infections, abscesses, granulomas in many organs, pyogenic
lymphadenitis
- treatment: long-term ATB administration, interferon gamma,
corticosteroids
COMPLEMENT DEFICIENCY
 C2, C3, C4 complement components deficiencies
- lead to an impaired opsonization, susceptibility to infections,
autoimune diseases
 C6, C7, C8, C9 complement components deficiencies
- lead to the autoimmune diseases – SLE, RA, sclerodermia and to
the neisserial infection
 MBL deficiencies
- lead to the respiratory infections and susceptibility to the
autoimune and allergy diseases
 Treatment: vaccination, ATB
HEREDITARY
ANGIOEDEMA
 pathophysiology
 clinical manifestations
 treatment
HEREDITARY ANGIOEDEMA
 the congenital AD complement disorder cased by the
defect on the chromosome 11
 leads to absence or functional deficiency of C1-inhibitor
 C4 a C2 complement components show a low level
during atack
 Type I - occurs in 85%
- an absence of C1-inhibitor
 Type II - occurs in 15%
- a functional deficiency of C1-inhibitor
 Secondary - SLE, lymfoma
HEREDITARY ANGIOEDEMA
 C1 esterase inhibitor deficiency leads to uncontrolled C1
activity and resultant production of a kinin that increases
capillary permeability
 Clinical feature: transient recurrent localized edema
 the triggering factors: injuries or surgical/stomatological
operations
 more offen occures in pregnancy
 laryngeal edema could be life-threatening, immediate
treatment is necessary !
TREATMENT
 Preventive – consist of an administration of androgens,
a-fibrinolytics
- before operation is necessary C1-INH concentrate or a
fresh frozen plasma administration
- stomatology procedures are performed in hospital
 Immediate - C1-INH concentrate or fresh frozen plasma
administration
 tracheotomy in severe larynx edema
 treatment with ACE inhibitors is contraindicated
ACQUIRED
IMMUNODEFICIENCIES
 causes
 mechanisms involved
 AIDS
ACQUIRED IMMUNODEFICIENCIES
 Acute and chronic viral infections – EBV, CMV, herpetic virus,
influenza, HIV
 Metabolic disorders – diabetes, renal failure, disorder of liver
function
 Autoimmune diseases – autoantibodies against immunocompetent
cells (neutrophils, lymphocytes)
 Allergic diseases
 Chronic GIT diseases, nephrotic syndrome
 Malignant diseases (leukemia, lymphoma, myeloma)
 Hypersplenism/asplenia, splenectomy – deficiency in generation
of antibodies against encapsulated microorganisms
(Pneumococcus, Neisseria)
 Burn, postoperative status, injuries
 Severe nutritional disorders, chronic stress
 Drug induced immunodeficiencies (chemotherapy),
immunosupression
 Chronic exposure to harmful chemical substances, ionizing
radiation
AIDS
 Acquired ImmunoDeficiency Syndrom
- caused by a retrovirus called human
immunodeficiency virus
- current incidence 40 mil.people, predominantly
in central Africa, CZ – about 1000 infected
people
 viral transmission occurs through:
- sexual intercourse
- contact with blood
- transplacentally, during the birth process or
through a breast milk
VIRUS HIV-1
 virion is consisted of a capside with marrow
protein - p24 and RNA
 RNA is copied into double-stranded DNA using
reverse transcriptase
 virus integrates to the human cell genome and
arise a provirus
 an activation of provirus leads to the replication
of viral nuclear acid and genesis of a virion that
goes through the cell membrane and caused the
lysis of cell
PRIMARY INFECTION
 Infection - begins by HIV-1 with a tropism for
macrofages:
- the membrane molecules of dendritic cells bind
glycoproteins on HIV-1 surface and transport viruses to
the lymphatic nodes (LN), where activated T cells are
infected
viruses are replicated in the lymphatic
nodes and transfer to the blood
 features: malaise, fever, pain of muscles and joints,
sweating, loss of appetite, vomiting, diarrhoea, rash,
lymphadenopathy
 Immunological findings: elevated C-reactive protein,
lymphopenia, decrease of CD4+ cells
 specific antibodies against HIV-1 don‘t generate
 identification of viruses is performed by PCR or by the
evidence of viral protein p24 presence
ASYMPTOMATIC PERIODE
 asymptomatic period – HIVs-1 with a tropism for
macrophages are changed into viruses with a tropism for
T cells and demage T cells (CD4+)
 viruses replicate in cell secondary lymphatic organs
- the period can last a several years
 lasting depends on:
- virus doses and virulence
- an individual condition of immune system an infected
person
- an acceleration occures by repeated infection of
different HIVs
AIDS
AIDS- Related Complex (ARC) presents with
lymphadenopathy and comes before fully
developed AIDS
Clinical features of AIDS :
- candidiasis of mouth and esophagous
mucose, colpitis
- oral leucoplakia, opportunistic infections
- Kaposi sarcoma, non-Hodgkin‘s lymfoma
VACCINE
 development of a vaccine is unsuccessful
due to:
- unsuccesful searching for a dominant viral antigen
- variability of the viruses HIV-1 in the course of time
- absence of an animal experimental model (even the
primate‘s infection course isn‘t identical with human)
TREATMENT
 Inhibitors of reverse transcriptase - 2 types
+
 Inhibitor of viral protease
=
 Therapy result to the inhibition of DNA synthesis, stop
the progress of the disease and prolong the life of HIV
infected persons
IMMUNOGLOBULIN REPLACEMENT
THERAPY
Indication
Contra-indication
Adverse reaction
IVIG is approved for treating
X-linked Bruton agammaglobulinemia
Common Variable ImmunoDeficiency
others
CONTRA-INDICATIONS
 Repeated severe side effects
 Selective IgA deficiency with anaphylactic reaction
to immunoglobuline
 Severe acute infection
IG ADMINISTRATION
 Intramuscullar – maximum dose 1,5 g IgG/
week
 Subcutaneous – total dose/month
400mg/kg, administration every week
 Intravenous - 400 mg/kg/month
AUTOIMMUNE DISORDERS
 examples
CLINICAL CATEGORIES
 systemic
- affect many organs and tissue
 organ localised
- affect predominantly one organ
accompained by affection of other organs
(nonspecific bowel diseases, celiatic disease,
AI hepatitis, pulmonary fibrosis)
 organ specific
- affect one organ or group of organs
connected with development or function
EXAMPLES OF SYSTEMIC
AUTOIMMUNE DISEASES
 examples
 autoantibodies
SYSTEMIC AUTOIMMUNE DISEASES
 Systemic lupus erythematosus
 Rheumathoid arthritis
 Sjögren‘s syndrome
 Dermatopolymyositis
 Systemic sclerosis
 Mixed connective tissue disease
 Antiphospholipid syndrome
 Vasculitis
 Sarcoidosis
SYSTEMIC LUPUS ERYTHEMATOSUS
 chronic, inflammatory, multiorgan disorder
 predominantly affects young women
 autoantibodies react with nuclear material and attack
cell function, immune complexes with dsDNA deposit
in the tissue
 general symptoms: include malaise, fever, weight
loss
 multiple tissue are involved including the skin,
mucosa, kidney, joints, brain and cardiovascular
system
 characteristic features: butterfly rash, renal
involvement, CNS manifestation, pulmonary fibrosis
DIAGNOSTIC TESTS
 a elevated ESR (erythrocyte sedimentation rate), low
CRP, trombocytopenia, leukopenia, hemolytic anemia,
depresed levels of complement (C4, C3), elevated
serum gamma globulin levels
AUTOANTIBODIES
 Autoantibodies: ANA, dsDNA (doublestranged), ENA (SS-A/Ro, SS-A/La), Sm,
against histones, phospholipids
RHEUMATOID ARTHRITIS
 chronic, inflammatory joint disease with systemic involvement
 predominantly affects women
 characterized by an inflammatory joint lesion in the synovial
membrane, destruction of the cartilage and bone, results in the joint
deformation
 clinical features: arthritis, fever, fatigue, weakness, weight loss
 systemic features: vasculitis, pericarditis, uveitis, nodules under
skin, intersticial pulmonary fibrosis
 diagnostic tests: elevated C- reactive protein
and ESR, elevated serum gammaglobulin levels
- autoantibodies against IgG = rheumatoid factor
(RF), a-CCP (cyclic citrulline peptid), ANA
- X-rays of hands and legs- show a periarticular
porosis, marginal erosion
Antiphospholipid syndrome
 autoimmune disease characterized by vein and
arterial thrombosis, repeated abortions
 accompanied by anti-phospholipid
autoantibodies (APA) and antibodies against
β2-glykoprotein I
EXAMPLES OF ORGAN- SPECIFIC
AUTOIMMUNE DISEASES
 diseases
 autoantibodies
ORGANOLEPTIC AUTOIMMUNE
DISEASES
Ulcerative colitis
Crohn‘s disease
Coeliac disease
Autoimmune hepatitis
Primary biliary cirhosis
Primary sclerotic cholangoitis
Pulmonary fibrosis
Ulcerative colitis
 chronic inflammation of the large intestine
mucose and submucose
 features: diarrhea mixed with blood and mucus
 extraintestinal features (artritis, uveitis)
 autoantibodies against pANCA, a- large
intestine
Crohn‘s disease
 the granulomatous inflammation of all
intestinal wall with ulceration and scarring
that can result in abscess and fistula
formation
 the inflammation of Crohn's disease the most
commonly affects the terminal ileum, presents
with diarrhea and is accompanied by
extraintestinal features - iridocyclitis, uveitis,
artritis, spondylitis
 antibodies against Saccharomyces
cerevisiae (ASCA), a- pancreas
Coeliac disease
 a malabsorption syndrome characterized by marked
atrophy and loss of function of the villi of the jejunum
 inflammatory bowell disease arise from gliadin
exposition
 autoantibodies against endomysium, the most
specific = tissue transglutaminaze; antibodies
against gliadin are nonspecific
 biopsy of the jejunum with findings of the villi atrophy
ORGAN SPECIFIC AUTOIMMUNE
DISEASES
 Autoimmune endocrinopathy
 Autoimmune neurological diseases
 Autoimmune cytopenia
 Autoimmune cutaneous diseases
 Autoimmune eye diseases
AUTOIMMUNE ENDOCRINOPATHY
 Hashimoto‘s thyroiditis
 Graves-Basedow disease
 Postpartum thyroiditis
 Diabetes mellitus I. type
 Addison‘s disease
 Autoimmune polyglandular syndrome
 Pernicious anemia
Hashimoto‘s thyroiditis
 thyroid disease result to hypothyroidism on the
base of lymphocytes and plasma cells infiltrate
 autoantibodies against thyroidal peroxidase (aTPO) and/or against thyroglobulin (a-TG)
Grave‘s disease
 thyrotoxicosis from overproduction of thyroid
hormone (patient exhibit fatigue, nervousness,
increased sweating, palpitations, weight loss,
exophtalmos)
 autoantibodies against thyrotropin receptor,
autoantibodies cause thyroid cells proliferation
Diabetes mellitus (insulin- dependent)
 characterized by an inability to process sugars in
the diet, due to a decrease in or total absence of
insulin production
 results from immunologic destruction of the
insuline- producing β-cells of the islets of
Langerhans in the pancreas
 autoantibodies against GAD- glutamic acid
decarboxylase = primary antigen),
autoantibodies anti- islet cell, anti- insulin
 islets are infiltrated with B and T cells
AUTOIMMUNE NEUROPATHY
 Guillain-Barré syndrome (acute idiopathic
polyneuritis)
 Myasthenia gravis
 Multiple sclerosis
Myasthenia gravis
 chronic disease resulting from faulty
neuromuscular transmission
 characterized by muscle weakness and fatigue
 the muscle weakness and neuromuscular
dysfunction result from blockage and depletion
of acetylcholin receptors at the myoneural
junction
 immunological findings: autoantibodies against
Ach receptors
 ptosis of the eye
Multiple sclerosis
 chronic demyeline disease with abnormal reaction T cells
to myeline protein on the base of mimicry between a virus
and myeline protein
 features: weakness, ataxia, impaired vision, urinary
bladder dysfunction, paresthesias, mental abberations
 autoantibodies against MOG (myelin-oligodendrocyte
glycoprotein)
 Magnetic resonance imaging of the brain and spine
shows areas of demyelination
 The cerebrospinal fluid is tested for oligoclonal bands,
can provide evidence of chronic inflammation of the
central nervous system
IMMUNOSUPRESSION
 non-specific treatment
examples of drugs
indication
risks
Immunosuppressants
 are drugs that inhibit or prevent activity of the
immune system
 They are used in immunosuppressive therapy to:
 Prevent the rejection of transplanted organs and
tissues
 Treat autoimmune diseases
 Treat some other non-autoimmune inflammatory
diseases (allergic asthma, atopic eczema)
Glucocorticoids
suppress the cell-mediated immunity
cytokine production
suppress the humoral immunity
side-effects: hypertension, dyslipidemia,
hyperglycemia, peptic ulcers,
osteoporosis, disturbed growth in children
 Drugs affecting the proliferation of both T cells
and B cells - Cyclophosphamide, Methotrexate,
Azathioprine, Mycophenolate mofetil
 Drugs blocking the activation of lymphocytes –
Tacrolimus, Sirolimus, Cyclosporin A
 Monoclonal antibodies - Daclizumab