L10-12: Microbiome and Immunopathologies Flashcards
Define: Microbiome
Collection of all genomes of microbes in an ecosystem
Define: Microbiota
Microbes that collectively inhabit a given ecosystem (symbiotic - commensals, NOT parasites)
Define: Pathobionts
Typically benign endogenous microbes with the capacity, under altered conditions to elicit pathogenesis
Prebiotics
Nutritional substrates that promote the growth of microbes that confer health benefits in the host
Probiotics
Live microbes that confer health benefits when administered in adequate amounts in the host
Synbiotics
Formulations consisting of a combination of probiotics and prebiotics
T or F:
In utero environment is sterile in healthy conditions.
False, DNA-based microbiota studies have detected bacterial species in the placentas of healthy mothers, in amniotic fluid of preterm infants and in meconium.
Key cells involved in Innate immunity
Monocytes, macrophages, NK cells, dendritic cells,
Role of dendritic cells in innate immunity
Recognition of microbial patterns (PRRs/TLRs)
Co-stimulation for T lymphocytes - instructing naive T cell to differentiate into different subsets
Cells/molecules involved in adaptive immunity
T lymphocytes - secretion of cytokines/chemokines
B lymphocytes - secretion of antibodies
T lymphocytes
Helper T (Th) Cytotoxic T (Tc) Regulatory T cells (Treg)
B lymphocytes
Produce Ab
B1/B2
Marginal zone B cells (MZB)
Follicular B cells
Immunoglobulin class types: primary vs. secondary response
Primary response predominantly IgM
Secondary response predominantly IgG, IgA
Most abundant Ig class type
IgG
GC/Follicular pathway
Typically associated with protein antigens
FDC presents Ag to B cell via the BCR which receives further help from a helper T cell via MHCII/TCR and CD40/CD40L interactions. This causes B cell to differentiate into plasma cells which produce Ab and memory B cells
Non-GC or extrafollicular pathway
T-independent antigens include large polysaccharides (pneumococcal PS) that can cross-link BCRs
No or few somatic hypermutations
Short-living plasma cells
No memory B cells
Regulatory T cells
Control inflammation, allergy and autoimmunity
Two types of Treg cells
- Naturally-occurring: CD4+CD25+FoxP3+ emerge from the thymus during development
- Inducible (can be induced in the periphery): CD4+CD25-FoxP3- (Tr1; IL-10) and CD4+CD25+/-
FoxP3+ (Th3; TGF-β)
Primary immunodeficiency
Genetic (inherited/present) at birth, approximately 150 different conditions, most rare
Symptoms may not appear until adulthood
Secondary immunodeficiency
Due to factors other than genetics e.g. HIV
Majority of primary immunodeficiencies are ___ related
antibody
Types of PID
• Antibody deficiencies (B-cell related):
– Common Variable Immune Deficiency (CVID)
– Specific (selective) antibody deficiency (SAD)
• T-lymphocyte disorders:
– Severe Combined Immune Deficiency (SCID)
– Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) (Treg)
• Innate deficiencies:
– IRAK-4 deficiency, CGD
Common Variable Immunodeficiency (CVID)
One of the most common PIDs - 1:50,000 affected. Characterized by low levels of serum Igs (hypogammaglobulinemia). Increased susceptibility to infections, predominantly lung. Enlarged spleen and lymph nodes, polyarthritis. Genetic causes unknown (10-25% inherited) - TACI (Transmembrane activator and calcium modulator and cyclophilin ligand interactor).
B cell function, not numbers, are affected. B cells fail to differentiate into plasma cells, and therefore lack of Ab production. Deficient memory B cells, and poor response to vaccines.
Treatment of CVID
Effective treatment allows patients to lead a normal life
- immunoglobulin replacement therapy (IVIg)
- antibiotics for chronic infections
Specific Antibody Deficiency (SAD)
Patients have normal Ig levels and normal Ig subclasses, however deficient in IgG2 important in responses to encapsulated bacteria (fails to produce protective Ab levels in response to polysaccharide antigens e.g. Streptococcus pneumoniae). Responses to protein Ag/vaccines normal.
Pneumococcal disease and SAD
Encapsulated bacteria – the capsule is a T-independent antigen (no T cell help). Significant pathogen causing pneumonia, otitis media and sinusitis. Also more serious invasive diseases such as meningitis and sepsis.
SAD – Laboratory Diagnosis
- Evaluate response to pneumococcal polysaccharide vaccine – 23 serotypes, response to at least half of serotypes (4-fold rise in IgG or >1.3μg/mL)
- Memory B cell numbers indicative of SAD
- Treated with IVIg and/or antibiotics
Severe Combined Immunodeficiency (SCID)
Rare, potentially fatal (‘bubble boy’), affects 1 in 58,000 (US data)
Lack of T-lymphocyte differentiation
– Lack of various T cell subsets
– Also B cells (through lack of T cell help)
Clinical presentation <6 months - diarrhoea, failure to thrive, pneumonia, persistent infections
Genetic defects identified associated with SCID
Most common is X-linked (45%) - common IL-2 receptor gamma chain mutation.
Also IL-7a, Jak3, CD3, CD45
Typical vs. Leaky SCID
Typical SCID - <300 autologous T cells/uL, lymphocyte function <10% of lower limit of normal range, deleterious SCID gene mutations
Leaky SCID - 300-1,499 autologous T cells, lymphocyte function 10-25%, hypomorphic SCID gene mutation
IPEX syndrome
Very rare condition caused by mutation in Foxp3
Lack of functional Treg cells
Multiple autoimmune disorders - diabetes, thyroiditis, haemolytic anaemia
IPEX pathology
- Absence of small bowel mucosa
- Inflammatory infiltrate in many organs
- Liver: fatty change
- Kidney: nephritis
- Skin: eczematous
- Duodenal villous atrophy
- No goblet cells
Chronic Granulomatous Disease
X-linked disorder, incidence 1:500,000
• Defect in intracellular bacterial killing by neutrophils and monocytes due to mutations in NADPH oxidase (> 400 known)
• Increased susceptibility to infections by ‘catalase’ organisms
IRAK-4 deficiency
Interleukin-1 receptor-associated kinase-4
• Extremely rare condition (48 worldwide as at 2010)
• Essential role in TLR and IL-1 receptor signalling
– Innate immune receptors for pathogen binding
– Affects NFκB signalling
– Inability to activate T cells
• Susceptible to pyogenic bacteria, not viruses, fungi
– predominately S. pneumoniae
• Vaccination can be beneficial
T cell tolerance mechanisms
Central tolerance occurs as T cell matures:
- Occurs in the thymus
- Positive selection - T cell has to recognise Ag in context of MHC
- Negative selection - affinity too high
Peripheral tolerance: – Occurs in peripheral tissues – ‘Regulatory’ responses involving mature T cells – Clonal anergy (lack of costimulation) – Ignorance (do not encounter Ag) – Suppression by cytokines (e.g. TGF-β) – Specific regulation (Treg induction) – Negative regulation (engagement of CTLA4)
B cell tolerance
Occurs in the bone marrow • Needs T cell tolerance to be intact • Self-reactive B cells can be: – Deleted when high affinity for antigen – Made anergic when antigen is soluble and at high concentration – Ignorance when lack of T cell help or low antigen concentration
Molecular mimicry
- Similar/identical epitopes between microbe and host
* Important when host Ag has important biological function eg. Streptococcal protein and bacterial endocarditis
Treg function and mechanism
Downregulation of receptors on APC or T cell directly in cell-cell contact inhibition
Secretion of immunosuppressive cytokines (IL-4, IL-10, TGF-β)
Milgrom and Witebsky’s criteria for
autoimmune diseases
- Lymphocytic infiltration of the target organ
- Presence of circulating autoantibodies and/or cellular immunity against the target organ
- Identification of the specific antigen(s)
- Production of humoral and/or cellular autoimmune response in animals sensitized by autologous antigen
- Close association with other autoimmune disorders
Diabetes
Group of diseases affecting insulin production and/or function
• Organ-specific autoimmune disease (Type 1)
• Targets the islets of Langerhans cells of the pancreas – important for insulin secretion
• Secondary damage to kidneys, eyes, nerves, blood vessels
• Onset from first year of life to older adulthood
Type 1 diabetes
5-10% of cases
• pancreatic β cell destruction
• Insulin deficiency
Type 2 diabetes
90-95% of cases
• ‘relative insulin deficiency’
• Inadequate production or peripheral resistance to insulin action
• Defect in signaling to Glut-4 from insulin receptors
Latent Autoimmune Diabetes in Adults (LADA)
A form of autoimmune diabetes which is diagnosed in
individuals who are older than the usual age of onset of type 1 diabetes.
• Also known as “Late-onset Autoimmune Diabetes of
Adulthood”, “Slow Onset Type 1” diabetes, and sometimes also “Type 1.5”
• LADA patients often thought to have Type 2 diabetes due to their age at diagnosis
Immunological events in diabetes
Failure of T cell tolerance:
– Defective clonal deletion (central)
– Regulatory response altered (peripheral)
Prior to clinical symptoms:
– Autoreactive T cells become activated
– Autoantibodies are produced
– Destroy islets of Langerhans in pancreas
– Occur over many years until nearly all beta cells affected
Autoantibodies in diabetes
Major autoantibodies are reactive to 4 islet autoantigens
(termed islet cell autoantibodies, ICA):
– Insulinoma-associated antigen-2 (ICA512)
– Insulin (micro-insulin autoantibodies, IAA)
– Glutamic acid decarboxylase 65 (GAD65)
– Zinc transporter 8 (ZnT8)
Genetics of type I diabetes
Major linkage to MHC class I and II genes (HLA), also linked to polymorphisms in CTLA4
Pathogenesis of type Idiabetes
Dysfunction in Tregs leading to breakdown in self-tolerance to islet-autoantigens
Pathology of type I diabetes
Insulitis (inflammatory infiltrate of T cells and macrophages)
β-cell depletion and islet atrophy
Systemic Lupus Erythematosus
- Multi-system chronic autoimmune disease - remitting and relapsing
- Type III hypersensitivity (immune complex) - anti-DNA complexes
- Acute or insidious in onset
- Many organs affected but main affected sites are kidneys and small blood vessels - Glomerulonephritis and skin involvement
Diagnostic feature of SLE
Antinuclear antibodies to Sm antigen and dsDNA
Malar rush
Photosensitivity
Pathogenesis of SLE
Genetics: HLA-DQ, complement components
Type III hypersensitivity reactions
- Immune complexes formed mainly in organs where blood is filtered e.g. kidneys, joints
- acute inflammatory response
- IgG and IgM (Complement fixing)
- phagocytosis
Treatment for SLE
Corticosteroids, immunosuppressants
Most common cause of death in SLE
renal failure
