JC89 (Microbiology) - Defense against microbes Flashcards
Components of innate immune system
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
3 complement activation pathways
Complement activation for membrane attack complex?
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)»_space; C5a (inflammation)»_space; C5b-C9 (membrane attack complex)
Components of adaptive immunity
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
Describe activation of innate immunity via PRRs
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
Functions of antibodies
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
5 types of antibodies and respective functions
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
Describe antibody structure and regions
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
Compare primary and secondary humoral response
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
Mechanisms that generate antibody diversity
Numerous IG genes with different V,D,J regions
Random recombination of VDJ regions
Junctional diversity
Combination pairing of heavy and light chains
Compare the function and cytokine production of T helper cell types
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
3 major types of cell-mediate cytotoxicity
Describe each process
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
3 modalities of chemotaxis of phagocytes
3 modalities for tagging cells for phagocytosis
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
Describe T-dependent Macrophage activation
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
Summarize the types of Th cells that activate neutrophils, Macrophages, B cells and Eosinophils/Basophils/ Mast cells
Th17»_space; Neutrophil
Th1»_space; Macrophage
Th1,2,17»_space; B cells
Th2»_space; Mast cells/ Basophils/ Eosinophils
Infections associated with complement defect (specific infections for each activation pathway) ***
Encapsulated bacteria only
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitides**
Vaccine BEFORE treating complement deficiency **
MENINGOCOCCAL VACCINE
Quantitative** Neutrophil dysfunction **
- Common causes
- Susceptible infections
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
Qualitative** neutrophil defect ***
- Most common cause
- specific physiological defect
- Susceptible infection and types of pathogens
Chronic granulomatous disease (CGD)
Mutation:
66% X-linked gp91phox
30% autosomal recessive form gp47phox
5% other mutations
Abnormal respiratory burst oxidase activity»_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…
Which immune deficiency is pathognomonic to ecthyma gangrenosum infection by P. aeruginosa?
Susceptible to what other infections
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»_space; cannot migrate into tissues)
Staphylococcus
Pseudomonas aeruginosa
Autoantibody against interferon-γ
Demographic
Physiological function of IFN-y
Susceptible infections
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
5 conditions causing impaired innate immunity **
Complement defect
Neutrophil quantitative defect
Chronic granulomatous disease - Neutrophil qualitative defect
Leukocyte adhesion deficiency syndrome
Autoantibody against IFN-y
6 conditions causing impaired humoral immunity**
Agammaglobulinemia Hyper-IgM syndrome IgG2 deficiency IgA deficiency Nephrotic syndrome Common variable immunodeficiency (CVID)
Impaired humoral immunity is susceptible to which infections ***
Prone to infection by encapsulated bacteria: Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitides Capnocytophagia canimorsus Babesia sp.
Agammaglobulinemia
- Defect
- Susceptible infection and causative pathogens
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
IgA deficiency
- Susceptible infections
- Precaution
Recurrent sinopulmonary infection (often asymptomatic)
Anaphylactic reaction if given IVIG (body reacts against IgA as IgA is never produced)
CVID
- Defect
- Susceptible infections
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
Impaired cell-mediated immunity
Susceptible infections
Most common opportunistic infection in advanced AIDS **
Pneumocystis pneumonia
Penicilliosis (disseminated)
Mycobacterium TB
Common AIDS-related infections
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
Cancers associated with AIDS ***
Cervical cancer (invasive) Kaposi sarcoma Burkitt’s lymphoma Immunoblastic lymphoma Primary lymphoma of the brain
Systemic conditions that affect immune function
- 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»_space; overwhelming Post-splenectomy infection (OPSI)
- Iron overload (repeated blood transfusion (e.g. thalassemia), ineffective iron chelation)
- Transplantation
Iron overload
- Why susceptible to infections
- Types of pathogens
Siderophilic bacteria thrive in hemochromatosis
Klebsiella
Salmonella
Yersinia
Rhizopus (mould)
Splenectomy/ functional hyposplenism
Why susceptible to infection?
Types of pathogens
Prevention of infections
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)
Examples of vaccines that elicit humoral immunity
Humoral immunity (elicit antibody response): Influenza vaccine, pneumococcal vaccine
Cell-mediated immunity, e.g. BCG (positive tuberculin skin test)
Types of active immunization methods
Active:
1. Whole organism: live attenuated (e.g. MMR) vs. inactivated (e.g. rabies)
- Toxoid (e.g. tetanus, pertussis, diphtheria/ DTaP-IPV vaccine)
- 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) - Recombinant proteins (e.g. HBV, HPV)
Types of passive immunization method
Passive: administer immunoglobulin
E.g. palivizumab = monoclonal antibody against RSV protein
Treatment options to reverse immunodeficient state
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
Treatment to modulate immune response/ immunomodulator options
- Naturally occurring cytokines e.g. pegylated IFN-a for Antiviral activity
- Glucocorticoids: Damp down inflammation to reduce detrimental effect
- IVIg: Bind to pathogens/ toxins, Immunomodulation
- Biologics
- Synthetic compounds with immunomodulation (e.g. cytokine-induced killer cell therapy for Mycobacterium abscessus bacteremia)
Examples of opportunistic infections treated by pegylated IFN
HCV
HBV
Kaposi sarcoma (HHV-8)
Condyloma acuminatum (HPV-6, HPV-11)
Examples of opportunistic infections treated by glucocorticoids
Pneumocystis pneumonia
TB meningitis
(Bacterial meningitis)
Chronic disseminated candidiasis
Examples of opportunistic infection treated by IVIg
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
Examples of biologics used for COVID-19
Tocilizumab - IL6 antagonist
Sarilumab - IL6 antagonist
Baricitinib - JAK inhibitor
Tofacitinib - JAK inhibitor
