Title: FAILURE OF HUMAN DEFENSE MECHANISMS
1FAILURE OF HUMAN DEFENSE MECHANISMS
2FAILURE 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
3MECHANISMS 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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7MECHANISMS 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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10MECHANISMS 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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13MECHANISMS 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
14MECHANISMS 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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21HUMAN 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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24HUMAN 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
25MECHANISMS 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)
26MECHANISMS 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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28TOXIC 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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31IMMUNODEFICIENCY 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
32COMPONENTS 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)
33EVALUATION 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
34PRIMARY 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
35PRIMARY 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)
36PRIMARY 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
37PRIMARY 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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39CASE 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
40CASE 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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45SELECTIVE 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
46SELECTIVE 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)
47SELECTIVE 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)
48SELECTIVE 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
49SELECTIVE 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
50SELECTIVE 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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54CORRECTION 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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56SECONDARY (ACQUIRED) IMMUNODEFICIENCY DISEASES
- Malnutrition
- Diseases
- Diabetes, nephrotic syndrome, protein-losing
enteropathy - Drugs
- Corticosteroids
- Hydrocortisone, methylprednisolone, prednisone
- Immunosuppressants
- Azathioprine, tacrolimus, cyclosporine A
57ACQUIRED 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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60CASE 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
61CASE 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
62CASE 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)
63CASE 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
64CASE STUDY (20 M) CBC WITH DIFF
-
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
65CASE 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
66CASE 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
67CASE 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
68CASE 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
69CASE 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
70CASE 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
71CASE 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
72CASE 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
73CASE 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
74CASE 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
75CASE 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
76CASE 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
77CASE 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)
78CASE 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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80PRINCIPLES 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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84CASE STUDY (20 M) IMMUNOLOGY (DAY 4)
-
-
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
85CASE STUDY (20 M) DIFFERENTIAL DIAGNOSIS
- Brutons X-linked agammaglobulinemia (XLA)
- Common variable immunodeficiency (CVID)
- Severe combined immunodeficiency (SCID)
- Omenn syndrome (OS)
86CASE STUDY (20 M) - MOLECULAR PATHOLOGY (FLOW
CYTOMETRY)
-
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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89CASE STUDY (20 M) FLOW CYTOMETRY
-
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)
90CASE STUDY (20 M) CLINICAL MANIFESTATION (DAY 5)
- Herpetiform vesicles on erythematous base
- Side of head
- Lower lip
- External ear
- CN V3 herpes zoster reactivation
91CASE STUDY (20 M) DISCHARGE DIAGNOSES (DAY 5)
- Pneumococcal meningitis with bacteremia
- Pseudomonas aeruginosa otitis externa
- Common variable immunodeficiency (CVID)
- CN V3 herpes zoster reactivation
92COMMON 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
93CVID 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
94CVID 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)
95CVID 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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