FAILURE OF HUMAN DEFENSE MECHANISMS

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FAILURE OF HUMAN DEFENSE MECHANISMS
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FAILURE OF HUMAN DEFENSE MECHANISMS

• Mechanisms of Failure
• Evasion and subversion of the immune system by
  pathogens
• Immunodeficiencies
• Inherited (Primary)
• Acquired (Secondary)
• Malnutrition
• Drugs
• Radiation
• Pathogens

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MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS

• Genetic variation (antigenic differences)
• Numerous different surface antigens (serotypes /
  serovars) without modification
• Streptococcus pneumoniae
• 90 serotypes (capsular polysaccharides)
• Salmonella species
• 2,500 serotypes (cell wall polysaccharides)
• Rhinoviruses
• 100 serotypes (capsid proteins)
• Poliovirus
• 3 serotypes (capsid proteins)

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MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS

• Genetic variation (antigenic differences)
• Few different surface antigens with frequent
  modification
• Influenza viruses
• Classification into types on nucleoprotein
• A, B and C
• Classification of Influenza A virus into
  subtypes
• Hemagglutinin (HA or H)
• Avian (16) and Human (3)
• Neuramindase (NA or N)
• Avian (9) and Human (2)
• Influenza A subtypes (H3N2, H1N1, H5N1)

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MECHANISMS OF GENETIC CHANGE IN INFLUENZA A VIRUS

• Antigenic Drift
• Point mutations in HA and NA genes
• No proofreading of replication
• Minor antigenic change resulting in new strains
• Antigenic Shift
• Re-assortment of gene segments from avian and
  human viruses in same host (swine or humans)
• Major antigenic change resulting in new subtype
  of Influenza A virus

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MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS

• Establishment of a dormant state (latency) with
  reactivation
• Blocking of antigen processing and presentation
• MHC I degradation
• Interference with proteasome
• Interference with TAP
• Interference with Tapasin
• Retention of MHC 1 in ER
• Interference with NKG2A receptor
• Inhibition of humoral immunity

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MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS

• Characteristic of the Herpesviruses
• Herpes simplex virus, type 1 (HSV-1)
• Herpes simplex virus, type 2 (HSV-2)
• Varicella-Zoster virus (VZV)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
• Human herpesvirus 6 (HHV-6)
• Human herpesvirus 7 (HHV-7)
• Human herpesvirus 8 (HHV-8)

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HUMAN HERPES VIRUS 8 (HHV-8)

• One of seven oncogenic viruses
• History of stealing human genes
• IL-6, BCL-2, cyclin D
• Etiologic agent
• Kaposis sarcoma
• Multicentric Castlemans Disease
• Non-malignant tumor in lymph nodes
• Hyperproliferation of B cells

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HUMAN HERPES VIRUS 8 (HHV-8)

• Target cell for latency
• B lymphocyte
• Mechanism of latency (genes and proteins)
• Cyclin D
• LANA (latency associated nuclear antigen)
• K 13
• Blocks Fas apotosis pathway
• Target cell for Kaposis sarcoma
• Spindle cell

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MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM

• Production of exotoxins (superantigens)
• Staphylococcus aureus
• Streptococcus pyogenes
• Staphylococcus aureus superantigens
• Toxic shock syndrome toxin-1 (TSST-1)
• 75 of cases (99 M and 40 NM)
• Staphylococcal enterotoxin B (SEB)
• 20 of cases
• Staphylococcal enterotoxin C (SEC)

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MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM

• Streptococcus pyogenes superantigens
• Streptococcus pyrogenic exotoxins A, B and C
• Exotoxins produced primarily from M types
• 1 and 3
• Mechanism of action
• Activation of 5 to 30 of T cells
• Cytokine storm

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TOXIC SHOCK SYNDROME (TSS)

• Staphylococcal TSS
• First reported in 1978 followed by outbreak in
  1980
• Clinical manifestations (acute onset)
• Fever (gt102 F), chills, headache
• Hypotension (lt90 mmHg)
• Diffuse macular erythroderma rash
• Myalgias
• Nausea, vomiting and diarrhea
• Cutaneous desquamation (palms and soles)

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IMMUNODEFICIENCY DISEASES

• A group of diseases where one or more components
  of the immune system are either absent or
  defective
• Classification
• Primary (Inherited)
• Gene defects may be autosomal or X-linked
• Secondary (Acquired)
• Malnutrition, diseases, drugs, radiation,
  microorganisms

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COMPONENTS OF THE IMMUNE SYSTEM AND CLINICAL
PRESENTATION IN IMMUNODEFICIENCY DISEASES

• Humoral
• Persons with history of recurrent infections with
  encapsulated bacteria
• Streptococcus pneumoniae
• Haemophilus influenzae
• Cellular (Cell mediated)
• Persons with history of recurrent infections with
  opportunistic pathogens
• Pneumocystis jiroveci (carinii)

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EVALUATION OF PATIENTS WITH IMMUNODEFICIENCY
DISEASES

• Humoral
• Measure antibody levels by nephelometry
• IgM
• IgG subclasses
• IgA subclasses
• Measure absolute number and percent of B cells by
  flow cytometry
• Cellular
• Measure absolute numbers and percentages of T
  lymphocytes by flow cytometry

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PRIMARY IMMUNODEFICIENCY DISEASES

• WHO currently recognizes 100 primary
  immunodeficiency diseases
• lt 20 account for gt90 of all cases
• General Classification
• Primarily humoral deficiency
• Primarily cellular deficiency
• Combined humoral and cellular deficiency
• Phagocyte dysfunction or deficiency
• Complement deficiency
• MHC deficiency

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PRIMARY IMMUNODEFICIENCY DISEASES

• Prevalence of primary immunodeficiency diseases
• B cell (50 to 60)
• T cell (5 to 10)
• B and T cells (20)
• Phagocytes (10 to 15)
• Complement (2)
• NK (lt 0.1)

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PRIMARY IMMUNODEFICIENCY DISEASES

• Most common primary immunodeficiency diseases
• B cell Selective IgA
  deficiency
• T cell DiGeorge
  syndrome
• ZAP-70
  deficiency
• B and T cells SCID
• Phagocytes Chronic
  granulomatous disease
• Complement Immune complex disease
• NK Viral
  infections and tumors

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PRIMARY IMMUNODEFICIENCY DISEASES

• Gene defects
• Autosomal recessive or dominant
• X-linked
• Examples
• CVID (autosomal dominant)
• Selective IgA (autosomal dominant)
• Hyper-IgM (autosomal recessive or X-linked)
• Classic complement (autosomal recessive)
• First PID described in 1952
• Brutons X-linked agammaglobulinemia

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CASE STUDY 13 YEAR OLD MALE

• Bone marrow transplantation (BMT) for SCID
• BM from sister was unmatched
• 3 months later developed
• Fever
• Nausea, vomiting and diarrhea
• Abdominal pain
• Intestinal bleeding
• Autopsy revealed
• Hundreds of intraabdominal malignant tumors

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CASE STUDY DAVID P. VETTER

• Parents David J and Carol Ann
• Children
• Katherine (1968)
• David J III (1970)
• Died of SCID at 7 months
• Advised of risk of another male child
• David P born on September 21, 1971
• Unmatched BMT on 12/21/83
• Died of SCID on 2/22/84

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SELECTIVE IgA DEFICIENCY

• Most common and mildest of PI
• Prevalence
• 1 in 700 caucasians
• 1 in 18,000 Japanese
• Majority of patients are asymptomatic
• Clinical presentation
• Recurrent sinopulmonary and GI disease, allergy,
  autoimmunity

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SELECTIVE IgA DEFICIENCY

• Incidence of allergy and asthma is increased
• Food allergy
• Asthma may be more severe
• Allergic rhinitis
• Incidence of autoimmune disease is increased
• Rheumatoid arthritis (RA)
• Systemic lupus erythematosus (SLE)
• Mechanism is unclear
• 30 of patients have Anti-IgA (IgG gt IgM gt IgE)

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SELECTIVE IgA DEFICIENCY

• IgA deficiency significant risk factor for
• Anaphylactic transfusion reactions
• Mechanism is unclear
• Classic anaphylaxis involves IgE
• Anti-IgA, IgG most prevalent
• Definition
• Deficiency (lt 7 mg/dL)
• Severe deficiency (lt0.05 mg/dL)

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SELECTIVE IgG DEFICIENCY

• Selective IgG subclass deficiency
• IgG2 in children
• IgG3 in adults
• Combined deficiency relatively common
• IgG2 with IgA
• IgG1 and IgG3
• IgG2 and IgG4
• Clinical presentation
• Recurrent upper and lower respiratory tract
  infections

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SELECTIVE IgG DEFICIENCY CASE STUDY

• 9 year old male presented to family physician by
  his mother for evaluation of short stature and
  recurrent infections
• Past medical history
• Recurrent URI and LRI with
• Streptococcus pneumoniae, Haemophilus influenzae,
  Influenza virus, Respiratory Syncytial Virus,
  Parainfluenza virus
• 2 to 3 each year since age 1
• Recurrent diarrhea since age 4

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SELECTIVE IgG DEFICIENCY CASE STUDY

• Laboratory results for total serum antibodies
• IgG of 6.0 gm/L (5.4 to 16.1 gm/L)
• IgA of 0.9 gm/L (0.7 to 2.5 gm/L)
• IgM of 0.6 gm/L (0.5 to 1.8 gm/L)
• Laboratory results for IgG subclasses
• IgG1 of 4.6 gm/L (3.6 to 7.3 gm/L)
• IgG2 of 0.1 gm/L (1.4 to 4.5 gm/L)
• IgG3 of 0.5 gm/L (0.3 to 1.1 gm/L)
• IgG4 of 0.2 gm/L (0.1 to 1.0 gm/L)

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CORRECTION OF GENETIC DEFECTS OF IMMUNE SYSTEM

• Many immunodeficiencies affect hematopoietic
  cells
• Correction of deficiency by transplantation of
• Bone marrow (hematopoietic stem cells)
• Success depends on degree of HLA matching between
  donor and recipient
• Major complication graft-versus-host disease
  (GVHD)
• Somatic gene therapy
• Functional copy of defective gene inserted into
  patients stem cells

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SECONDARY (ACQUIRED) IMMUNODEFICIENCY DISEASES

• Malnutrition
• Diseases
• Diabetes, nephrotic syndrome, protein-losing
  enteropathy
• Drugs
• Corticosteroids
• Hydrocortisone, methylprednisolone, prednisone
• Immunosuppressants
• Azathioprine, tacrolimus, cyclosporine A

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ACQUIRED IMMUNODEFICIENCY DISEASES

• Radiation
• Microorganisms
• Human T-cell lymphotropic virus, type I (HTLV-I)
• Mycobacterium leprae
• Lepromatous leprosy
• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV)
• Human immunodeficiency virus (HIV)

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CASE STUDY 20 YEAR OLD MALE

• Presented to ER of Southeast Regional Medical
  Center in Lumberton, NC
• Headache, fever, chills, AMS and nuchal rigidity
• Blood cultures collected, but lumbar puncture was
  unsuccessful
• Treated with single 2 gram dose of ceftriaxone
• Transferred to New Hanover Regional Medical
  Center in Wilmington, NC

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CASE STUDY (20 M) PHYSICAL EXAMINATION

• VITAL SIGNS
• Temperature 100 F, PR 92, RR 20, BP 120/60
• HEENT AND NECK
• Pupils equal, round and light reactive
• Nuchal rigidity is positive
• LYMPH NODES
• No lymphadenopathy
• ABDOMEN
• Soft. No distention, tenderness, organomegaly
• EXTREMITIES
• Bilateral upper and lower clubbing
• NEUROLOGIC
• Babinski is negative and Kernig is positive
  

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CASE STUDY 20 YEAR OLD MALE

• Past medical history
• Recurrent infections (age 10)
• Sinusitis
• Pneumococcal pneumonia and bacteremia
• Specimens collected for culture at NHRMC
• Blood, CSF and ear drainage
• Treatment at NHRMC
• Ceftriaxone (2 grams IV q12) and vancomycin (1
  gram IV q12)

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CASE STUDY (20 M) COMPREHENSIVE METABOLIC PANEL
(CMP)

• Patient
  Reference
• Glucose 172 72 -
  112 mg/dL
• BUN 7
  7 - 18 mg/dL
• Creatinine 0.7 0.5 -
  1.2 mg/dL
• Sodium 139 136 -
  146 mmol/L
• Potassium 3.8 3.7 -
  5.2 mmol/L
• Chloride 106 98 -
  108 mmol/L
• Calcium 8.3 8.5 -
  10.5 mg/dL
• Total Protein 4.8 6.1 -
  8.0 mg/dL
• Albumin 2.6 3.5 -
  4.8 g/dL
• Bilirubin (T) 0.6 0.0 -
  1.0 mg/dL
• AST 7
  15 - 37 U/L
• ALT 22
  19 - 55 U/L
• Alk Phos 63 50
  - 136 U/L

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CASE STUDY (20 M) CBC WITH DIFF

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  Patient Reference
• WBC 19.8 4.8 -
  10.8 K/uL
• RBC 4.2 4.9 -
  6.1 M/uL
• Platelets 278 145 -
  400 K/uL
• HGB 11.5 14.0 -
  18.0 g/dL
• HCT 33.6 40
  - 52
• Neutrophils 85 40 -
  74
• Lymphocytes 7 15 - 47
  
• Monocytes 7 0 -
  12
• Eosinophils 0 0
  - 6
• Basophils 0 0
  - 2

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CASE STUDY (20 M) URINE DRUG SCREEN

• PCP
  Negative
• Benzodiazepine Negative
• Cocaine Negative
• Amphetamine Negative
• THC
  Negative
• Opiates
  Negative
• Barbiturates Negative
• Methadone Negative
• Tricyclic Antidepressants Negative

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CASE STUDY (20 M) COAGGULATION/HEMATOLOGY

• Patient
  Reference
• PT 16.6 10.7
  - 13.5 seconds
• INR 1.93 0.86 -
  1.34 seconds
• PTT 42.8 25
  - 38 seconds
• Fibrinogen 711 160 -
  440 mg/dL
• Haptoglobin 425 43 -
  212 mg/dL
• Sed rate 60
  0 - 15 mm/hr

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CASE STUDY (20 M) CEREBROSPINAL FLUID

• Glucose 0 40 - 70
  mg/dL
• Protein 314 15 - 45
  mg/dL
• Lactic acid 17.6 lt 2.8
  mmol/L
• WBC 568
  uL
• RBC 373
  uL
• Neutrophils 73
  
• Lymphocytes 11
  
• Monocytes 16
  
• VDRL Negative
  Negative

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CASE STUDY (20 M) MICROBIAL ANTIGENS (CSF)

• Haemophulus influenzae, type B
  Negative
• Streptococcus pneumoniae
  Negative
• Streptococcus agalactiae (GBS)
  Negative
• Neisseria meningitidis (C, W135)
  Negative
• Neisseria meningitidis (A, Y)
  Negative
• Neisseria meningitidis (B)/ E.coli
  Negative
• Cryptococcus neoformans
  Negative

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CASE STUDY (20 M) CULTURE AND SMEAR (CSF)

• Routine
• 2 to 6 WBC/HPF
• No organisms seen on gram stained smear
• Acid-fast bacilli
• No acid fast bacilli (AFB) seen on fluorochrome
  stained smear
• Fungus
• No fungal elements seen on PAS stained smear

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CASE STUDY (20 M) CBC WITH DIFF (DAY 2)

• Patient
  Reference
• WBC 14.5 4.8 - 10.8
  K/uL
• RBC 3.73 4.6 - 6.1
  M/uL
• Platelets 302 145 - 400
  K/uL
• HGB 10.0 14.0 - 18.0
  g/dL
• HCT 30.0 40.0 -
  52.0
• Neutrophils 76 40 - 74
  
• Lymphocytes 16 15 - 47
  
• Monocytes 8 0 - 12
  
• Eosinophils 0 0 - 6
  
• Basophils 0 0 - 2
  

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CASE STUDY (20 M) CMP (DAY 2)

• 
  Patient Reference
• Glucose 129 72 -
  112 mg/dL
• Protein(T) 5.2 6.1
  - 8.0 g/dL
• Albumin 2.3 3.5 -
  4.8 g/dL
• AST 2.0
  15 - 37 U/L
• All other analytes within reference
  ranges

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CASE STUDY (20 M) CSF STUDIES (DAY 3)

• 
  Patient Reference
• Glucose 34
  40 - 70 mg/dL
• Protein 100
  15 - 45 mg/dL
• WBC 576
  uL
• RBC 14
  uL
• Neutrophils 42
  
• Lymphocytes 28
  
• Monocytes 30
  
• Bacterial antigens Negative
  Negative

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CASE STUDY (20 M) CSF CULTURE AND SMEAR (DAY 3)

• Routine
• 0 to 1 WBC/HPF
• No organisms seen on gram stained smear
• Acid-fast bacilli
• No acid fast bacilli seen on fluorochrome stained
  smear
• Fungus
• No fungal elements seen on PAS stained smear

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CASE STUDY (20 M) MOLECULAR MICROBIOLOGY (DAY 3)

• Cerebrospinal fluid (CSF) by PCR
• HSV-1 and HSV-2 DNA
  Negative
• Enterovirus RNA
  Negative
• Borrelia burgdorferi DNA
  Negative

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CASE STUDY (20 M) MICROBIOLOGY AT NHRMC (DAY 3)

• Ear drainage growth
• Pseudomonas aeruginosa
• Blood cultures
• Negative at day 3 and day 5
• Cerebrospinal fluid cultures
• Negative

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CASE STUDY (20 M) BLOOD CULTURES (SRMC-DAY 3)

• Streptococcus pneumoniae
• Penicillin G Resistant
• Ceftriaxone Resistant
• Azithromycin Resistant
• Trim/Sulfa Resistant
• Chloramphenicol Susceptible
• Moxifloxacin Susceptible
• Tetracycline Susceptible
• Vancomycin Susceptible

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CASE STUDY (20 M) - IMMUNOLOGY (DAY 3)

• Consultation between infectious disease and
  clinical microbiology
• Monospot test
• RPR
• Antinuclear antibody (ANA)
• Complement (T)
• HIV-1/2 antibody
• Serum protein electrophoresis (SPE)

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CASE STUDY (20 M) - IMMUNOLOGY (DAY 3)

• Monospot test
  Negative
• RPR
  Negative
• Antinuclear antibody (ANA) Negative
• Complement (T) 48
  U/mL 31 66 U/mL
• HIV-1/2 antibody
  Invalid
• Serum protein electrophoresis Severe
  hypogammaglobulinemia

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PRINCIPLES OF HIV-1/2 ANTIBODY TEST

• Lateral flow immunochromatographic procedure
• Antigens and antibody immobilized onto
  nitrocellulose
• membrane in T and C zones
• Test (T) Zone
• Synthetic peptides from HIV envelope region
• Control (C) Zone
• Goat anti-human IgG
• Developer solution
• Facilitates flow of specimen onto test strip
• Rehydrates protein-A gold colorimetric reagent

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CASE STUDY (20 M) IMMUNOLOGY (DAY 4)

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• 
  Patient
  Reference
• Immunoglobulin A (IgA) lt 15.0
  81 - 463 mg/dL
• Immunoglobulin G (IgG) lt 60.0
  694 - 1618 mg/dL
• Immunoglobulin M (IgM) lt 5.0
  48 - 271 mg/dL

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CASE STUDY (20 M) DIFFERENTIAL DIAGNOSIS

• Brutons X-linked agammaglobulinemia (XLA)
• Common variable immunodeficiency (CVID)
• Severe combined immunodeficiency (SCID)
• Omenn syndrome (OS)

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CASE STUDY (20 M) - MOLECULAR PATHOLOGY (FLOW
CYTOMETRY)

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  Patient Reference
• CD3/CD5 79
  52 84
• CD4 lymphocytes 45 30
  61
• CD8 lymphocytes 30 12
  42
• CD19/CD20 18
  5 25
• CD3-/CD56 3
  5 30

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CASE STUDY (20 M) FLOW CYTOMETRY

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  Percent Cells/uL
  Reference
• Lymphs (CD45)
  1540 1000 - 4800
• T-Lymphs (CD3) 1175
  690 2540
• T-Lymphs 76
  55 84
• (CD3/CD45)
• T-Helper lymphs
  687 410 1590
• (CD3CD4)
• T-Helper lymphs 45
  31 60
• (CD3CD4/CD45)

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CASE STUDY (20 M) CLINICAL MANIFESTATION (DAY 5)

• Herpetiform vesicles on erythematous base
• Side of head
• Lower lip
• External ear
• CN V3 herpes zoster reactivation

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CASE STUDY (20 M) DISCHARGE DIAGNOSES (DAY 5)

• Pneumococcal meningitis with bacteremia
• Pseudomonas aeruginosa otitis externa
• Common variable immunodeficiency (CVID)
• CN V3 herpes zoster reactivation

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COMMON VARIABLE IMMUNODEFICIENCY (CVID)

• Most prevalent primary immunodeficiency
• Heterogeneous group of immunologic disorders
• Unknown etiology
• Characterized by marked deficiency of
• IgG and IgA
• IgM and T-cell dysfunction
• Generalized lymphadenopathy and splenomegaly

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CVID PATHOPHYSIOLOGY

• Number of mechanisms for defective antibody
  production
• B-cell defects
• Differentiation of B-cells into plasma cells
• T-cell defects
• Low level expression of CD40 ligand

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CVID EPIDEMIOLOGY

• Prevalence of 1 case in 10,000 to 50,000
  population
• Female to male ratio of 1
• All races
• Age at diagnosis
• 1 to 5 years
• 16 to 20 years
• 21 years and greater (60)

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CVID COMPLICATIONS AND RISKS

• Recurrent infections
• Upper and lower respiratory tract
• Streptococcus pneumoniae and Haemophilus
  influenzae
• Herpes labialis (HSV)
• Herpes zoster (VCV)
• Autoimmune diseases (RA, AHA, ATP)
• Malignancy
• Non-Hodgkins lymphoma
• Malignant lymphoma

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