IgG and IgM based immunopathological reaction (reaction of hypersensitivity type II).

IgG and IgM based immunopathological reaction (reaction of hypersensitivity type II).

antibodies produced by the immune response bind to antigens on the patient's own cell surfaces

•= antibody-dependent

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)

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 hypogamaglobulinemiaCVID - Common Variable

ImmunoDeficiencySelective 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

IndicationContra-indicationAdverse 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 (double-stranged), 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 colitisCrohn‘s diseaseCoeliac diseaseAutoimmune hepatitisPrimary biliary cirhosisPrimary sclerotic cholangoitisPulmonary 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 (a-

TPO) 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 treatmentexamples of drugs

indicationrisks

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 immunityside-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