Immunodeficiencies and autoimmune diseases

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Immunodeficiencies andautoimmune diseases

• Martin Liška

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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

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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

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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

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I. Primary immunodeficiencies phagocytic cell
defects

• 1/ Quantitative decreased numbers of
  granulocytes neutrophil elastase mutation
• Congenital chronic agranulocytosis
• Cyclic agranulocytosis (neutropenia)

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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

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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 (Jobs) syndrome
• Recurrent cold staphylococcal abscesses,
  chronic eczema, otitis media
• Extremely high serum IgE levels

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II. Primary immunodeficiencies B cell disorders

• Brutons 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

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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

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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

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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

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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 !

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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

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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

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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

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A.I.D.S. - Treatment

• Reverse transcriptase inhibitors (e.g.zidovudine)
• Protease inhibitors - block the viral protease
  enzyme
• Combined drug therapy
• Antimicrobial agents

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AUTOIMMUNE DISEASES
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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

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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)

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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

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SYSTEMIC AUTOIMMUNE DISEASES

• Systemic lupus erythematosus
• Rheumathoid arthritis
• Sjögrens syndrome
• Dermatopolymyositis
• Systemic sclerosis
• Mixed connective tissue disease
• Vasculitis

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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

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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

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AUTOANTIBODIES

• Autoantibodies ANA, dsDNA (double-stranded), ENA
  (SS-A/Ro, SS-A/La), Sm, against histones,
  phospholipids

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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

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SJÖGRENS 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

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Dermatopolymyositis

• a connective-tissue disease related to
  polymyositis (PM) that is characterized by
  inflammation of the muscles and the skin.

Gottron's sign is an erythematous, scaly eruption
occurring in symmetric fashion over the MCP and
interphalangeal joints
Heliotrope rash is a violaceous eruption on the
upper eyelids, often with swelling
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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)

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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

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Immunological findings

• ANA, ENA - anti-Scl-70 (fluorescence of
  nucleolus), anti-centromers

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Mixed connective tissue disease

• combines features of polymyositis, systemic lupus
  erythematosus, scleroderma, and dermatomyositis
  (overlap syndrome)
• Symptoms 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)

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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

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Vasculitis

• p- ANCA (myeloperoxidase) positivity
  (Polyarteritis nodosa, Churg- Strauss,
  Microscopic polyarteritis nodosa)
• c- ANCA (serin proteinase) positive (Wegener
  
• granulomatosis, Churg- Strauss syndrome)

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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

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ORGANOLEPTIC AUTOIMMUNE DISEASES

• Ulcerative colitis
• Crohns disease
• Autoimmune hepatitis
• Primary biliary cirhosis
• Pulmonary fibrosis

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Ulcerative colitis

• chronic inflammation of the large intestine
  mucosa and submucosa
• features diarrhea, bloody and mucus stools
• extraintestinal features (arthritis, uveitis)
• Autoantibodies pANCA, a- large intestine

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Crohns 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

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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

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AUTOIMMUNE ENDOCRINOPATHY

• Hashimotos thyroiditis
• Graves-Basedow disease
• Diabetes mellitus I. type
• Addisons disease
• Autoimmune polyglandular syndrome

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Hashimotos 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)

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Graves 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

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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

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Polyglandular autoimmune syndrome

• combination of several different AI
  endocrinopathies
• autoantibodies appear in according with the
  connected disorders

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AUTOIMMUNE NEUROPATHY

• Guillain-Barré syndrome (acute idiopathic
  polyneuritis)
• Myasthenia gravis
• Multiple sclerosis

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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-oligodendrocyt
  e 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

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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

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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).

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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

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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.

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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

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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

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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