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Immunodeficiencies. Humoral innate immunity - complement, MBL acquired immunity immunoglobulins (B lymphocytes)Cell mediated immunity innate immunity phagocytes - acquired immunity T lymphocytesPrimary congenital,
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1. Immunodeficiencies andautoimmune diseases Martin Liška
2. Immunodeficiencies Humoral – innate immunity - complement, MBL
acquired immunity – immunoglobulins (B lymphocytes)
Cell mediated immunity – innate immunity – phagocytes
- acquired immunity – T lymphocytes
Primary – congenital, genetically defined, symptoms predominantly
at an early age
Secondary – the onset of symptoms at any age
chronic diseases
the effects of irradiation
immunosuppression
surgery, injuries
stress
3. Immunodeficiencies – critical life periods in respect to symptoms onset Newborn age - severe primary disorders of cell mediated immunity
6 mth. – 2 yrs. – severe humoral immunodeficiencies
cong./transient
3 - 5 yrs. – transient and selective humoral immunodeficiencies,
secondary immunodeficiencies
15 – 20 yrs. – hormonal instability, thymus involution, life-style changes,
some typical infections
first symptoms of CVID
Middleage – often excessive workload, stress
first symptoms of autoimmune disorders (also immunodeficiency)
Advanced and old age – rather symptoms of severe secondary immunodeficiencies,
repercussion of functional disorders
4. Immunodeficiencies – major clinical features Antibodies - microbial infections (encapsulated bacterias)
respiratory - pneumonia, sinusitis, otitis
GIT – diarrhea
Complement – microbial infections (pyogenic), sepsis
various systems affection
edema (HAE) – C1-INH deficiency
T lymphocytes - bacterial, fungal, viral
GIT – diarrhoea
respiratory – pneumonia, sinusitis
Phagocytes - abscesses, recurrent purulent skin infections
granulomatous inflammations
5. I. Primary immunodeficiencies – phagocytic cell defects 1/ Quantitative – decreased numbers of granulocytes –neutrophil elastase mutation
Congenital chronic agranulocytosis
Cyclic agranulocytosis (neutropenia)
6. I. Primary immunodeficiencies – phagocytic cell defects
2/ Qualitative – phagocytes functional disorders, various enzyme deficits, inability of phagocytes to degrade the ingested material
a/ Chronic Granulomatous Disease (CGD)
Approximately in 60% X-linked
Enzymatic inability to generate toxic oxygen metabolites (H2O2) during oxygen consumption) - result of defect in neutrophilic cytochrome b (part of complex containing NADPH oxidase)
Inability to kill bacteria such as Staph.aureus, Pseud.aeruginosa that produce the enzyme catalase
Clinical features: granulomas in many organs
Treatment: long-term ATB administration
7. I. Primary immunodeficiencies – phagocytic cell defects b/Myeloperoxidase deficiency
Susceptible to Staph.aureus or C.albicans infections
c/Chédiak-Higashi syndrome
Clinical features: recurrent, severe, pyogenic infections (streptococcal, staphylococcal)
Defective intracellular killing of bacteria (neutrophils contain abnormal giant lysosomes
d/HyperIgE (Job’s) syndrome
Recurrent “cold” staphylococcal abscesses, chronic eczema, otitis media
Extremely high serum IgE levels
8. II. Primary immunodeficiencies – B cell disorders Bruton’s X-linked hypogamaglobulinemia
Blockage in the maturation of pre-B lymphocytes into B lymphocytes (tyrosine kinase defect)
Undetectable or very low serum levels of Ig
Pneumonia, pyogenic otitis, complicated sinusitis, increased occurrence of pulmonary fibrosis
Treatment: life-long IVIG substitution
CVID – Common Variable ImmunoDeficiency
B cell functional disorder, mostly low levels of IgG and IgA
Symptoms’ onset between 2nd and 3rd decade
Recurrent respiratory tract infections (pneumonia)
Treatment: IVIG substitution
9. II. Primary immunodeficiencies – B cell disorders Selective IgA deficiency
Disorder of B cell function
Recurrent mild/moderate infections (respiratory, GIT, urinary tract) or asymptomatic
Risk of reaction to live attenuated vaccines or generation of anti-IgA antibodies after a blood transfusion
Selective IgG subclasses or specific IgG deficiency
B cell function disorder
Onset of symptoms in childhood, mostly respiratory tract infections caused by encapsulated bacteria (H.influenzae, Pneumococci)
Transient hypogammaglobulinemia of infancy
10. III. Primary immunodeficiencies – T cell disorders diGeorge syndrome
Disorder of prethymocytes maturation due to absence of thymus (disorder of development of 3rd and 4th branchial pouch)
Congenital heart diseases
The onset of symptoms after the birth – hypocalcemic spasms and manifestations of cong.heart disease
Immunodeficiency could be only mild, the numbers of T lymphocytes later usually become normal
Treatment symptomatic
11. IV. Primary immunodeficiencies – combined defects of T and B cells SCID – Severe Combined ImmunoDeficiency
X-linked recessive or AR disease, combined disorder of humoral and cell mediated immunity
Severe disorder (patients often die during first 2 years of life), symptoms’ onset soon after the birth (severe diarrhoea, pneumonia, meningitis, BCGitis)
Immunological features: typically lymphopenia and thymus hypoplasia
Forms: AR form – often enzymatic deficiency (ADA, PNP) that leads to accumulation
of metabolites toxic to DNA synthesis (lymphocytes)
X-linked form – disorder of stem-cell
Treatment: ATB, IVIG
BMT is of critical significance
Wiskott-Aldrich syndrome
trombocytopenia, eczema, recurrent infections (encapsulated microbes), decreased IgM levels
12. V. Primary immunodeficiencies – complement system disorders Hereditary angioedema (HAE)
Absence or functional deficiency of C1-inhibitor
Anaphylactoid reactions with skin and/or mucosal (oral, laryngeal, gut) edemas caused by C3a a C5a
Injuries or surgical/stomatological operations are mostly the triggering factor
Laryngeal edemas could be life-threatening, immediate treatment is necessary !
Treatment: preventive – androgens, EACA
immediate – C1-INH concentrate or fresh frozen plasma
administration
Secondary forms also exist !
13. Secondary immunodeficiencies Acute and chronic viral infections – infectious mononucleosis, influenza
Metabolic disorders – diabetes mellitus, uremia
Autoimmune diseases – autoantibodies against immunocompetent cells (neutrophils, lymphocytes); autoimmune phenomena also after administration of certain drugs (e.g. oxacilin, quinidine)
Chronic GIT diseases
Malignant diseases (leukemia)
Hypersplenism/asplenia
Burn, postoperative status, injuries
Severe nutritional disorders
Chronic infections
Ionizing radiation
Drug induced immunodeficiencies (chemotherapy)
Immunosupressive therapy
Chronic stress
Chronic exposure to harmful chemical substances
14. Secondary immunodeficiencies Chronic fatigue syndrome
First, it is necessary to exclude all chronic diseases which can lead to fatigue:
autoimunity
malignancy
focal infection
neurological disorders
metabolic disorders
depression
15. Secondary immunodeficiencies - A.I.D.S. Caused by retrovirus HIV 1 or HIV 2
Virus has a tropism for cells bearing CD4 surface marker (Th CD4+ lymphocytes); also affects macrophages and CNS cells
Viral genome transcribes into human DNA and infected cell provides viral replication
Transmission: sexual intercourse
contact with blood
endouterine (mother – fetus, breast milk)
Phases: acute (flu-like sy)
asymptomatic – several years, viral replication
symptomatic – infections, autoimmune disorders, malignancy,
allergy
final – systemic breakdown, opportune infections
16. A.I.D.S. - Treatment Reverse transcriptase inhibitors (e.g.zidovudine)
Protease inhibitors - block the viral protease enzyme
Combined drug therapy
Antimicrobial agents
17. AUTOIMMUNE DISEASES
18. Autoimmune disease Results from a failure of self-tolerance
Immunological tolerance is specific unresponsiveness to an antigen
All individuals are tolerant of their own (self) antigens
19. AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY the diseases are chronic and usually irreversible
incidence: 5%-7% of population, higher frequencies in women, increases with age
factors contribute to autoimmunity:
- internal (HLA association, polymorphism of cytokine genes, defect in genes regulating apoptosis, polymorphism in genes for TCR a H immunoglobulin chains, association with immunodeficiency, hormonal factors)
- external (infection, stress by activation of neuroendocrine axis and hormonal dysbalance, drug and ionization through modification of autoantigens)
20. CLINICAL CATEGORIES
systemic
- affect many organs and tissue
organoleptic
- affect predominantly one organ accompanied by affection of other organs (inflammatory bowel diseases, celiac disease, AI hepatitis, pulmonary fibrosis)
organ specific
- affect one organ or group of organs connected with development or function
21. SYSTEMIC AUTOIMMUNE DISEASES Systemic lupus erythematosus
Rheumathoid arthritis
Sjögren‘s syndrome
Dermatopolymyositis
Systemic sclerosis
Mixed connective tissue disease
Vasculitis
22. SYSTEMIC LUPUS ERYTHEMATOSUS chronic, inflammatory, multiorgan disorder
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
23. DIAGNOSTIC TESTS a elevated ESR (erythrocyte sedimentation rate), low CRP, trombocytopenia, leucopenia, hemolytic anemia, decreased levels of complement compounds (C4, C3), elevated serum Ig levels, immune complexes in serum
24. AUTOANTIBODIES Autoantibodies: ANA, dsDNA (double-stranded), ENA (SS-A/Ro, SS-A/La), Sm, against histones, phospholipids
25. RHEUMATOID ARTHRITIS chronic, inflammatory disease with systemic involvement
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
26. SJÖGREN‘S SYNDROME chronic inflammatory disease affecting exocrine glands
the primary targets are the lacrimal and salivary gland duct epithelium
general features: malaise, weakness, fever
primary syndrome - features: dry eyes and dry mouth, swollen salivary glands, dryness of the nose, larynx, bronchi and vaginal mucosa, involvement kidney, central and periferal nervous system, arthritis
secondary syndrome – is associated with others AI diseases (SLE, RA, sclerodermia, polymyositis, primary biliary cirhosis,AI thyroiditis)
autoantibodies against ENA (SS-A, SS-B),
ANA, RF
The Schirmer test - measures the production
of tears
28. Dermatopolymyositis Elevated creatine phosphokinase (CPK)
muscle biopsy (a mixed B- and T-cell perivascular inflammatory infiltrate, perifascicular muscle fiber atrophy)
EMG (electromyogram)
autoantibodies - ENA (Jo-1)
29. Systemic sclerosis sclerosis in the skin or other organs
Diffuse scleroderma (progressive systemic sclerosis) is the most severe form,
involves skin, will generally cause internal organ damage (specifically the lungs and gastrointestinal tract)
The limited form is much milder
The limited form is often referred to as CREST syndrome (CREST is an acronym for the five main features: Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyly, Telangiectasia
30. Immunological findings ANA, ENA - anti-Scl-70 (fluorescence of nucleolus), anti-centromers
31. Mixed connective tissue disease combines features of polymyositis, systemic lupus erythematosus, scleroderma, and dermatomyositis (overlap syndrome)
Causes : joint pain/swelling, malaise, Raynaud phenomenon, muscle inflammation and sclerodactyly (thickening of the skin of the pads of the fingers)
Distinguishing laboratory characteristics:
a positive, speckled anti-nuclear antibody (ANA) and anti-U1-RNP antibody (ENA)
32. Vasculitis characterized by inflammatory destruction
of vessels leading to thrombosis and aneurysms
proliferation of the intimal part of blood-vessel wall and fibrinoid necrosis
affect mostly lung, kidneys, skin
diagnostic tests: elevated ESR, CRP, leucocytosis, biopsy of affected organ (necrosis, granulomas), angiography
33. Vasculitis
p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyarteritis nodosa)
c- ANCA (serin proteinase) positive (Wegener
granulomatosis, Churg- Strauss syndrome)
34. Classification Large vessel vasculitis (Takayasu arteritis, Giant cell (temporal) arteritis)
Medium vessel vasculitis (Polyarteritis nodosa, Wegener's granulomatosis, Kawasaki disease)
Small vessel vasculitis (Churg-Strauss arteritis, Microscopic polyarteritis, Henoch-Schönlein purpura)
Symptoms: fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction
35. ORGANOLEPTIC AUTOIMMUNE DISEASES
Ulcerative colitis
Crohn‘s disease
Autoimmune hepatitis
Primary biliary cirhosis
Pulmonary fibrosis
36. Ulcerative colitis chronic inflammation of the large intestine mucosa and submucosa
features: diarrhea, bloody and mucus stools
extraintestinal features (arthritis, uveitis)
autoantibodies against pANCA, a- large intestine
37. Crohn‘s disease the granulomatous inflammation of whole 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
38. AUTOIMMUNE HEPATITIS type I – association with autoantibodies against
smooth muscles SMA, ANA, ANCA, SLA
type II – autoantibodies against microsomes LKM-1
= liver-kidney microsomes
type III – autoantibodies against SLA (solubile liver
antigen)
type IV – overlap syndrome with PBC –
autoantibodies against mitochondries AMA
39. AUTOIMMUNE ENDOCRINOPATHY
Hashimoto‘s thyroiditis
Graves-Basedow disease
Diabetes mellitus I. type
Addison‘s disease
Autoimmune polyglandular syndrome
40. 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 thyroglobulinu (a-TG)
41. Grave‘s disease thyrotoxicosis from overproduction of thyroid hormone (patient exhibit fatigue, nervousness, increased sweating, palpitations, weight loss,
exophtalmus)
autoantibodies against thyrotropin receptor,
autoantibodies cause thyroid cells proliferation
42. 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 ß-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
43. Polyglandular autoimmune syndrome combination of several different AI endocrinopathies
autoantibodies appear in according with the connected disorders
44. AUTOIMMUNE NEUROPATHY
Guillain-Barré syndrome (acute idiopathic polyneuritis)
Myasthenia gravis
Multiple sclerosis
45. Multiple sclerosis chronic demyelinizing 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
46. AUTOIMMUNE CYTOPENIA
AI hemolytic disease- autoantibodies against membrane erythrocyte antigens
AI trombocytopenia - autoantibodies against
trombocyte antigens (GPIIb/IIIa)
AI neutropenia - autoantibodies against
membrane neutrofil antigens
47. Immunosuppressive drugs 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 (bone marrow, heart, kidney, liver)
Treat autoimmune diseases or diseases that are most likely of autoimmune origin (rheumatoid arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, pemphigus, ulcerative colitis).
Treat some other non-autoimmune inflammatory diseases (allergic asthma, atopic eczema).
48. Glucocorticoids suppress the cell-mediated immunity- act by inhibiting genes that code for various cytokines (e.g.IL-2)
decrease cytokine production reduces the T cell proliferation.
suppress the humoral immunity
side-effects: hypertension, dyslipidemia, hyperglycemia, peptic ulcers, osteoporosis, disturbed growth in children
49. Drugs affecting the proliferation of both T cells and B cells Cyclophosphamide -very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias
high doses cause pancytopenia and hemorrhagic cystitis
Methotrexate is a folic acid antagonist, acts during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle; used in the treatment of autoimmune diseases (RA, Crohn's disease) and in transplantations.
50. Drugs affecting the proliferation of both T cells and B cells Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially leucocytes; SLE, RA, sclerosis multiplex, transplantation
51. Drugs blocking the activation of lymphocytes Cyclosporin A- inhibits calcineurin, which is responsible for activating the transcription of interleukin-2; inhibits cytokines production and interleukin release
Used to prevent rejection reactions
Side effects: nephrotoxicity, neurotoxicity, hypertension, dyslipidemia, hyperglycemia
52. Monoclonal antibodies Monoclonal antibodies are directed towards exactly defined antigens
Daclizumab - acts by binding the IL-2a receptor's a chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival
used in the prophylaxis of the acute organ rejection after the bilateral kidney transplantation