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MBBS IV - Junior Clerkship WCS > JC89 (Microbiology) - Defense against microbes > Flashcards

JC89 (Microbiology) - Defense against microbes Flashcards

1
Q

Components of innate immune system

A

Epithelial barrier:
 Skin
 Gastrointestinal
 Respiratory tract

Antimicrobial peptides in mucosa, e.g. cathelicidins, defensins

Phagocytic cells (neutrophils, macrophages, Natural killer cells)

Cytokines (interleukin etc.)

Complements

Platelet

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2
Q

3 complement activation pathways

Complement activation for membrane attack complex?

A

plasma proteins activated by microbes:
 Classical pathway: Ag- Ab complex bound by C1
 Alternative pathway: Ag bound by C3b
 Lectin pathway: mannose bound by lectin

Production of C3 promotes destruction, inflammation:
 C3a: inflammation
 C3b (osponization)&raquo_space; C5a (inflammation)&raquo_space; C5b-C9 (membrane attack complex)

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3
Q

Components of adaptive immunity

A

Humoral immunity:
- B cell, plasma cell for antibody production

Cellular immunity:

  • B lymphocytes
  • T lymphocytes: CD4+ T helper cells, CD8+ Cytotoxic T cells, T-reg cells
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4
Q

Describe activation of innate immunity via PRRs

A

Pathogen antigens enter body

pattern recognition receptor (PPR) on host immune cell surface (e.g. Toll-like receptor, Nod-like receptor) recognize pathogen-associated molecular patterns (PAMPs) e.g. polysaccharides, dsRNA

Induce innate immune response by cytokines, complements

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5
Q

Functions of antibodies

A

A. Bind to pathogen/toxin:

  • Neutralize toxin/ virus (e.g. neutralize tetanus toxins)
  • Direct antimicrobial activity
  • Complement activation
  • Opsonization for neutrophil and macrophage destruction
  • Antibody-dependent cellular cytotoxicity (ADCC) for Cytotoxic T cell response

B. Bind to host cell/ tissues for immunomodulation

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6
Q

5 types of antibodies and respective functions

A 
IgM (pentamer)
First Ig class produced in primary responses. Activated complement system, low affinity to pathogens

IgG (monomer)
Appears after IgM in large titer in acute infection, Rises before IgM in repeated infection

IgA (monomers and dimer connected by J chain)
Secreted by epithelial cells for Mucosal immunity e.g. saliva, milk, tracheobronchial secretions

IgE: Binds to surface of mast cells, basophils and eosinophils for allergic reactions; mediate immunity against helminthic parasites

IgD: On B cell surface for signaling, Maintain quiescent state of autoreactive B cells, Mucosal homeostasis

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7
Q

Describe antibody structure and regions

A

2 heavy chains bind to 2 light chains with disulfide bonds

2 Variable regions (VH and VL) - Varied amino acid sequence and 3D structure for antigen recognition, consists of hypervariable and framework regions

1 Constant region (Fc) : engage in effector functions

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8
Q

Compare primary and secondary humoral response

A

Primary:

  • Long lag phase (7-10days), Antigen-specific naive B cells undergo clonal selection and differentiation into plasma cells and memory B cel;s
  • Antigen-specific Ab levels increase and declines
  • IgM released first, then IgG

Secondary:

  • Short lag phase, Antigen-specific Memory B cells quickly expand into plasma and memory cells
  • Rapid exponential production of Ab, with longer plateau before tapering
  • Much high antibody infinity than primary response
  • Mainly IgG
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9
Q

Mechanisms that generate antibody diversity

A

Numerous IG genes with different V,D,J regions

Random recombination of VDJ regions

Junctional diversity

Combination pairing of heavy and light chains

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10
Q

Compare the function and cytokine production of T helper cell types

A

Th1 - Produce IFN-γ
- Phagocyte-mediated (macrophage) response vs Intracellular microbes (e.g. Mycobacterium tuberculosis), protozoa

Th2 - Produces IL4, IL5, IL13
- IgE, Esosinophil/ Mast cell/ Basophil mediated response against parasites and helminth infection

TH17 - Produces IL17
- Neutrophil activation against Extracellular bacterial and fungal infections

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11
Q

3 major types of cell-mediate cytotoxicity

Describe each process

A

Cytotoxic T lymphocyte CTL -mediated killing

  • MHC Class I restricted (Intracellular antigens, pathogens)
  • MHC1 - TCR - CD8 and CD80/86 - CD28 binding
  • Perforins (pores, osmotic lysis), Granzyme (apoptosis), Lymphotoxin (apoptosis) release from CTL and MQ

Antibody-dependent Cell-mediated cytotoxicity (ADCC)

  • Antibody constant region receptor FcR recognizes Ab tagged on abnormal cell
  • Large Granular Lymphocytes/ NL cells release cytotoxic factors to kill abnormal cell (virus infected/ microbes)

Natural Killer (NK) cell-mediated killing

  • KIR and KAR signals balance
  • Kill with no antigen specificity
  • Kill tumor cells, grafts and virus-infected cells
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12
Q

3 modalities of chemotaxis of phagocytes

3 modalities for tagging cells for phagocytosis

A

Chemotaxis:

  • Bacterial component e.g. fMLP
  • Complement product e.g. C5a
  • Locally released chemokines and cytokine by WBCs e.g. IL-12, TNFa

Tag:

  • Fc receptor-mediated: recognize constant region of Ab tagged onto pathogen
  • Complement receptor mediated: complement tagged
  • Mannose receptor-mediated: fucose and oligosaccharides on pathogen surface
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13
Q

Describe T-dependent Macrophage activation

A

2 signals:
CD40L-CD40
TCR- MHCII

both signals needed to activate IFN-y release to MQ
MQ response by increase MHC expression, Lysosome formation, Phago-lysosome fusion and inducible iNOS to destroy engulfed pathogens

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14
Q

Summarize the types of Th cells that activate neutrophils, Macrophages, B cells and Eosinophils/Basophils/ Mast cells

A

Th17&raquo_space; Neutrophil

Th1&raquo_space; Macrophage

Th1,2,17&raquo_space; B cells

Th2&raquo_space; Mast cells/ Basophils/ Eosinophils

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15
Q

Infections associated with complement defect (specific infections for each activation pathway) ***

A

Encapsulated bacteria only

 Streptococcus pneumoniae
 Haemophilus influenzae
 Neisseria meningitides**

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16
Q

Vaccine BEFORE treating complement deficiency **

A

MENINGOCOCCAL VACCINE

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17
Q

Quantitative** Neutrophil dysfunction **

  • Common causes
  • Susceptible infections
A

Most common causes:
 Hematological malignancy (leukemia)
 Drugs, e.g. chemotherapy, prolonged beta-lactam antibiotics (induce myelosuppression)
 Post-transplant

Susceptible infections:
1) Fungal: Candida, Aspergillus, Fusarium, Mucor…

2) Pyogenic bacterial infection and bacteremia:
Gram-positive cocci:
 Staphylococcus epidermidis, S. aureus
 Streptococcus viridans (esp. mitis)
 Enterococcus spp
Gram-negative rods/ bacilli:
 Escherichia coli
 Klebsiella pneumoniae
 P. aeruginosa

18
Q

Qualitative** neutrophil defect ***

  • Most common cause
  • specific physiological defect
  • Susceptible infection and types of pathogens
A

Chronic granulomatous disease (CGD)
Mutation:
 66% X-linked gp91phox
 30% autosomal recessive form gp47phox
 5% other mutations

Abnormal respiratory burst oxidase activity&raquo_space; defects in intracellular killing

Susceptible to pathogens with strong catalase reaction (can neutralize free radicals/ superoxides in phagosome)
 Gram-positive: S. aureus, Nocardia
Gram-negative facultative anaerobe: Serratia marcescens
Non-fermenter: Burkholderia cepacia, Chromobacterium violaceum
Aspergillus

Presentation:
Abscesses e.g. skin or retropharyngeal abscess or perianal abscess
Lymphadenitis e.g. cervical lymphadenitis
Diseminnated TB, BCG infection
Rheumatological diseases - dactylitis, arthritis…

19
Q

Which immune deficiency is pathognomonic to ecthyma gangrenosum infection by P. aeruginosa?

Susceptible to what other infections

A

Leukocyte adhesion deficiency (LAD) syndromes
CD18/ Beta-integrin defect

Features:
- Paper thin scars, skin abscess, poor wound healing (Staphylococcus aureus)
- Ecthyma gangrenosum (multiple ulcers with pus and soft tissue necrosis) (Pseudomonas aeruginosa)
- Chronic periodontitis
- omphalitis

Extremely high neutrophil count (Affected inflammatory cells cannot adhere within the vasculature&raquo_space; cannot migrate into tissues)

 Staphylococcus
 Pseudomonas aeruginosa

20
Q

Autoantibody against interferon-γ

Demographic
Physiological function of IFN-y
Susceptible infections

A

Adults-onset (acquired); Asians

Interferon-γ:
Produced by both:
 Innate: NK cells
 Adaptive: Th1, CD8
Activate macrophages to kill intracellular microbes

Susceptible infections: intracellular pathogens
Bacteria:
- MOTT (Mycobacterium chelonae)
- Non-typhoidal salmonella
Dimorphic fungi:
- Penicillium marneffei
VZV

21
Q

5 conditions causing impaired innate immunity **

A

Complement defect

Neutrophil quantitative defect

Chronic granulomatous disease - Neutrophil qualitative defect

Leukocyte adhesion deficiency syndrome

Autoantibody against IFN-y

22
Q

6 conditions causing impaired humoral immunity**

A 
Agammaglobulinemia
Hyper-IgM syndrome
IgG2 deficiency
IgA deficiency
Nephrotic syndrome
Common variable immunodeficiency (CVID)
23
Q

Impaired humoral immunity is susceptible to which infections ***

A 
Prone to infection by encapsulated bacteria:
 Streptococcus pneumoniae 
 Haemophilus influenzae
 Neisseria meningitides
 Capnocytophagia canimorsus
 Babesia sp.
24
Q

Agammaglobulinemia

  • Defect
  • Susceptible infection and causative pathogens
A

Btk protein defect
Panhypogammaglobinemia, no B cells in peripheral blood
Tx: IvIg

1) No IgA in mucosa: recurrent resp. Infection and bronchiectasis
 Sinusitis
 Otitis media
 Pneumonia
Pathogens:
 Streptococcus pneumoniae
 Haemophilus influenzae
 Meningococci
 Mycoplasma

2) Intestinal infections: recurrent diarrhea
 Salmonella, Shigella, Campylobacter
 Giardia
 Rotavirus

25
Q

IgA deficiency

  • Susceptible infections
  • Precaution
A

 Recurrent sinopulmonary infection (often asymptomatic)

 Anaphylactic reaction if given IVIG (body reacts against IgA as IgA is never produced)

26
Q

CVID
- Defect
- Susceptible infections

A

ICOS, CD19 defect
Confirm: Low serum IgG,A,E and poor Ab response to Vaccines

Infections:
Sinopulmonary: recurrent bronchitis, sinusitis, otitis media, pneumonia
Gastrointestinal
Systemic bacterial infections

Other diseases:
Autoimmune disease
 Increased risk of GI malignancy, lymphoma
Granulomatous disease
 Malabsorption

All by encapsulated bacteria as with all impaired humoral immunity

27
Q

Impaired cell-mediated immunity

Susceptible infections

A
28
Q

Most common opportunistic infection in advanced AIDS **

A

Pneumocystis pneumonia

Penicilliosis (disseminated)

Mycobacterium TB

29
Q

Common AIDS-related infections

A

Poor T cell response, moist susceptible to intracellular pathogen infection

Bacteria:
MTB, M. avium complex, M. kansasii
MOTT
Salmonella septicaemia

Virus:
CMV
HSV
JC virus > PML (progressive multifocal leukoencephalopathy)

Fungal:
Peniciliosis
PCP
Candidiasis
Cryptococcus
Histoplasmosis
Coccidioidomycosis

Parasite:
Toxoplasmosis
Cryptosporidiosis
Isosporiasis

HIV related encephalopathy, wasting syndrome

30
Q

Cancers associated with AIDS ***

A 
 Cervical cancer (invasive)
 Kaposi sarcoma
 Burkitt’s lymphoma
 Immunoblastic lymphoma
 Primary lymphoma of the brain
31
Q

Systemic conditions that affect immune function

A
  • Breaks in physical barriers e.g. skin, mucosa
  • Extremes of age
  • Pregnancy (dampen immunity to tolerate fetus)
  • Malnutrition e.g. Zinc deficiency
  • DM
  • Autoimmune diseases
  • Liver cirrhosis
  • Splenctomy/ functional hyposplenism&raquo_space; overwhelming Post-splenectomy infection (OPSI)
  • Iron overload (repeated blood transfusion (e.g. thalassemia), ineffective iron chelation)
  • Transplantation
32
Q

Iron overload

  • Why susceptible to infections
  • Types of pathogens
A

Siderophilic bacteria thrive in hemochromatosis

 Klebsiella
 Salmonella
 Yersinia
 Rhizopus (mould)

33
Q

Splenectomy/ functional hyposplenism

Why susceptible to infection?
Types of pathogens
Prevention of infections

A

Splenectomy:
 Cannot clear encapsulated bacteria
 Cannot produce opsonizing antibody

Overwhelming sepsis by encapsulated bacteria:
Streptococcus pneumoniae/ Pneumococcus (most common)
Haemophilus influenzae type b
 Neisseria meningiditis
 (More in children:) Capnocytophaga canimorsus (e.g. licked by dogs), Babesia sp.

Vaccination:
Streptococcus pneumoniae/ Pneumococcal vaccine
 Influenza vaccine
 (Haemophilus influenzae type b)
 (Neisseria meningitidis)

34
Q

Examples of vaccines that elicit humoral immunity

A

Humoral immunity (elicit antibody response): Influenza vaccine, pneumococcal vaccine

Cell-mediated immunity, e.g. BCG (positive tuberculin skin test)

35
Q

Types of active immunization methods

A

Active:
1. Whole organism: live attenuated (e.g. MMR) vs. inactivated (e.g. rabies)

  1. Toxoid (e.g. tetanus, pertussis, diphtheria/ DTaP-IPV vaccine)
  2. Soluble capsular material, e.g. Pneumococcal vaccine
    a. Polysaccharide vaccine: T-cell-independent B cell response
    b. conjugate vaccine (polysaccharide Ag is coupled to an immunogenic protein carrier for better B cell response)
  3. Recombinant proteins (e.g. HBV, HPV)
36
Q

Types of passive immunization method

A

Passive: administer immunoglobulin

E.g. palivizumab = monoclonal antibody against RSV protein

37
Q

Treatment options to reverse immunodeficient state

A

Glucose control in diabetes mellitus
HAART (antiretroviral therapy) for HIV
G-CSF to increase neutrophil count in patients with neutropenia
IVIG in patients with CVID (common variable immunodeficiency), hypogammaglobulinemia

38
Q

Treatment to modulate immune response/ immunomodulator options

A
  1. Naturally occurring cytokines e.g. pegylated IFN-a for Antiviral activity
  2. Glucocorticoids: Damp down inflammation to reduce detrimental effect
  3. IVIg: Bind to pathogens/ toxins, Immunomodulation
  4. Biologics
  5. Synthetic compounds with immunomodulation (e.g. cytokine-induced killer cell therapy for Mycobacterium abscessus bacteremia)
39
Q

Examples of opportunistic infections treated by pegylated IFN

A

 HCV
 HBV
 Kaposi sarcoma (HHV-8)
 Condyloma acuminatum (HPV-6, HPV-11)

40
Q

Examples of opportunistic infections treated by glucocorticoids

A

 Pneumocystis pneumonia
 TB meningitis
 (Bacterial meningitis)
 Chronic disseminated candidiasis

41
Q

Examples of opportunistic infection treated by IVIg

A

 Toxic shock syndrome due to Group A Streptococcus/ Staphylococcus
 Parvovirus infection in immunocompromised patients

Prophylaxis:
 Following exposure against VZV, CMV, HAV, measles…
 In patients with humoral immunodeficiencies

42
Q

Examples of biologics used for COVID-19

A

Tocilizumab - IL6 antagonist

Sarilumab - IL6 antagonist

Baricitinib - JAK inhibitor

Tofacitinib - JAK inhibitor

MBBS IV - Junior Clerkship WCS (131 decks)

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