Immune overview, autoimmunity, and primary immune deficiencies Flashcards
Th1: cytokines produced
IFN-gamma
Th2: cytokines produced
IL-4, IL-5, IL-13
Th17: cytokines produced
IL-17, IL-22, chemokines
IFN-gamma and IL-12 induce what Th subtype?
Th1
IL-4 induces what Th subtype?
Th2
TGF-beta, IL-6, IL-1, and IL-23 induce what Th subtype?
Th17
Th1: immunologic reactions triggered
- macrophage activation 2. stimulation of IgG 3. antibody production
Th2: immunologic reactions triggered
- IgE production 2. activation of mast cells 3. activation of eosinophils
Th17: immunologic reactions triggered
- recruitment of neutrophils 2. recruitment of monocytes
Th1 is used by the host to defend against what?
intracelluar microbes
Th2 is used by the host to defend against what?
helminthic parasites
Th17 is used by the host to defend against what?
extracellular bacteria, fungi
Th1: role in disease
immune-mediated chronic inflammatory diseases (often autoimmune)
Th2: role in disease
allergies
Th17: role in disease
immune-mediated chronic inflammatory diseases (often autoimmune)
Describe each of the four major Ig subtypes
- IgM: low affinity, activates the classical complement pathway 2. IgG: neutralizes microbes and toxins, opsonizes antigens, activates classical complement pathway, responsible for antibody-dependent cellular cytotoxicity (ADCC) 3. IgA: mucosal transport, neutralizes mucosal microbes and toxine 4. IgE: ADCC of parasites, responsible for allergy reaction (mast cell degranulation)
Name the three complement pathways and what is responsible for activating them
- Classical pathway: IgM and IgG 2. Alternative pathway: C3b 3. Lectin pathway: mannose-binding lectin (MBL)
All complement pathways converge on what?
Activation of C5-C9, forming the membrane attack complex (MAC)
Describe APECED
Autoimmune polyendocrinopathy candidiasis ectodermal dystropy (APECED): Cause: AIRE gene defect -> example of failure of central tolerance Autoimmune adrenal and parathyroid disease Can also induce autoimmune hypothryroidism, hypogonadism, vitiligo, and pernicious anemia Also associated with fungal infections (candidiasis)
APECED is caused by what?
AIRE gene defect -> thymic medullary cells do not express self-antigen -> self-reactive T-cells are not deleted (failure of central tolerance)
Name the major clinical features of APECED
- bradycardia, hypotension (salt craving) 2. bronzed skin 3. thrush in mouth 4. abnormal nails
Lab findings of APECED
- low cortisol 2. low calcium, low PTH 3. hyponatremia, hypocalcemia, hyperkalemia
Describe ALPS
Autoimmune lymphoproliferative syndrome (ALPS): Cause: mutations in Fas or FasL -> example of failure of peripheral tolerance Widespread lymphadenopathy, splenomegaly, and autoimmune cytopenias (hemolytic anemia and thrombocytopenia). High IgG, IgA, and IgM common Increased percentages of double-negative T-cells
Clinical features of ALPS
- Pallor 2. diffuse lymphadenopathy 3. splenomegaly
Lab findings of ALPS
- hypergammaglobulinemia 2. Coomb’s positive hemolytic anemia 3. Flow cytometry shows increase double-negative T-cells
ALPS is caused by what?
Mutations in Fas or FasL -> failure of peripheral tolerance
Describe IPEX
Immune dysregulation, polyendocrinopathy, X-linked (IPEX): Due to mutation in Foxp3 gene (loss of Treg cells) Requires bone marrow transplant -> deadly otherwise Affects boys in infancy Hypergammaglobulinemia Presents with IBD, severe eczema and food allergies, T1DM, thyroiditis, autoimmune hemolytic anemia, thrombocytopenia
Clinical features of IPEX
- Diffuse eczematous rash 2. Cachexia 3. Pallor
Lab findins for IPEX
- Hypergammaglobulinemia 2. Coomb’s positive hemolytic anemia 3. IgE ~14,000IU/dl (nl < 200) 4. positive skin allergy test to all (most) foods 5. low serum albumin, iron deficiency 6. hyperglycemia, glucosuria, low insulin
Treg cells express which gene?
Foxp3
What is the Foxp3 gene?
Expressed in Treg cells. It is mutated in IPEX syndrome.
Which gene family is most frequently associated with autoimmune disease?
HLA
Ankylosing spondylitis is strongly associated with which MHC allele?
HLA-B27
Which MHC allele is frequently associated with a wide variety of autoimmune disorders, including: RA, T1DM, pemphigus vulagaris?
HLA-DR4
Name the 4 types of hypersensitivity reactions:
Type 1: immediate sensitivity (IgE-mediated) Type 2: antibody-mediated Type 3: immune-complex-mediated Type 4: delayed-type hypersensitivity (T-cell mediated)
Allergic rhinits, asthma, eczema, and food allergies are ell examples of what type of hypersensitivity reaction?
Type 1
Type 1 hypersensitivity is mediated by what?
IgE
Myasthenia gravis and Graves disease are examples of what type of hypersensitivity?
Type 2
A multinucleate cell found an an inflamed muscle is called a(n)
Aschoff body
What are the criteria for Acute Rheumatic Fever?
J(heart)NES criteria: J = Joints (heart) = heart (carditis) N = nodules E = erythema marginatum S = sydenham’s chorea 2 major or 1 major + 2 minor criteria + supporting evidence of preceding GAS infection major: carditis, polyarthritis, sydengam’s chorea, erythema marginatum, subQ nodules minor: fever, arthralgia, elevated acute phase reactants, prolonged PR interval
Acute rheumatic fever is caused by what?
Molecular mimicry of heart muscle by S. pyogenes virulence factors (M proteins) following GAS infection
Treatment for ARF
Penicillin prophylaxis
ARF is what type of hypersensitivity reaction?
Type 2
Goodpasture’s syndrom is what type of hypersensitivity reaction?
Type 2
Name treatment options for type 2 hypersensitivity reactions
- Non-life-threatening: high dose IVIG, corticosteroids, Rituximab 2. Life-threatening: plasmapheresis
Type 3 hypersensitivity is mediated by what?
Immune complexes (Ab:Ag)
Systemic Lupus Erythematosus is an example of what type of hypersensitivity?
Type 3
What are the 11 criteria for SLE? How many of them must be present for Dx of SLE?
At least 4 of 11 criteria must be met for Dx: 1. malar rash 2. discoid rash 3. photosensitivity 4. oral/nasal ulcers 5. arthritis 6. serositis 7. cerebritis (including seizures) 8. nephritis 9. ANA 10. Ab to dsDNA or Anti-Sm 11. Autoimmune cytopenias (ITP, AIHA)
Immune complexes generated in SLE primarily affect what tissues/organ systems?
- Kidney 2. Joints 3. Skin
Early-onset SLE is associated with what?
Early complement defects (C1q, C2, C4)
SLE: antibody specificity and major clinicopathologic manifestations
- DNA, nucleoproteins, others (“anything”) 2. nephritis, arthritis, vasculitis
Polyarteritis nodosa: antibody specificity and major clinicopathologic manifestations
- Hepatitis B virus (due to chronic HepB infection) 2. Vasculitis
Poststreptococcal glomerulonephritis: antibody specificity and major clinicopathologic manifestations
- Streptococcal wall antigens 2. nephritis
Serum sickness: antibody specificity and major clinicopathologic manifestations
- Various protein antigens 2. Systemic vasculitis, nephritis, arthritis
Arthus reaction: antibody specificity and major clinicopathologic manifestations
- Various protein antigens 2. Cutaneous vasculitis
What is the Arthus reaciton?
A Type 3 hypersensitivity reaction following intradermal injection of an antigen. Produces local vasculitis due to deposition of IgG:Ab immune complexes, which in turn recruit PMNs and local mast cell degranulation. Sometimes associated with vaccines.
List the two major processes behind Type 4 hypersensitivity reactions
- Delayed-type hypersensitivity (Th1 delayed-type hypersensitivity and Th17-mediated inflammatory reaction) 2. T-cell-mediated lysis
Rheumatoid arthritis is an example of what type of hypersensitivity reaction?
Type 4
What are the three main inflammatory cytokines released by monocytes and macrophages?
IL-1, IL-6, TNF
True or false: B-cells may be involved in the Type 4 hypersensitivity response
True
What type of hypersensitivity reaction is Dermatomyositis?
Type 4
Clinical manifestations of Dermatomyositis
- Heliotropic rash 2. Gottron’s papules (scaly rashes, PIP joints and hands) 3. Proximal muscle weakness 4. Capillary changes (dilation, dropout hemorrhage -> especially apparent on nail beds) 5. High AST/ALT
Dermatomyositis vs. Polymyositis
Dermatomyositis: Perifascicular atrophy: CD4/B/PC/MP-mediated infarct of tissue due to microvascular injury and compensatory capillary dilation Polymyositis: diffuse muscle fiber death due to CD8-mediated attach of muscle fibers
T1DM: hypersensitivity type?
Type 4 - pancreatic islet antigens
Rheumatoid arthritis: hypersensitivity type?
Type 4 - unknown joint antigen
Multiple sclerosis: hypersensitivity type?
Type 4 - CNS myelin proteins
Inflammatory bowel disease: hypersensitivity type?
Type 4 - unknown intestinal antigen
Tuberculosis: hypersensitivity type?
Type 4 - microbial proteins
Name the disease associated with the following autoimmune mechanisms/antigens: 1. auto-reactive T-cells and activated macrophages that specifically de-myelinate CNS motor and sensory neurons 2. Autoantibodies directed against platelets 3. antibodies to Schwann cell membranes with ascending paralysis 4. Auto-antibodies against thyroglobulin leading to thyroid inflammation and hypothyroidism 5. Enteropathy related to gluten in food
- Multiple sclerosis 2. Thrombocytopenia 3. Guillain-Barre Syndrome 4. Hashimoto’s thyroiditis 5. Celiac disease
Name the disease associated with the following autoimmune mechanisms/antigens: 1. Antibodies against dsDNA, histones, and other nuclear proteins -> nephritis, cerebritis, serositis, dermatitis, etc 2. Autoantibodies against joint antigens 3. Autoantibodies to myosin following infection with GAS (especially joints and heart)
- Systemic lupus erythematosus 2. Rheumatoid arthritis 3. Rheumatic fever
Allergy is also known as what?
Type 1 hypersensitivity reaction
Name 4 main suspicion criteria for primary immune deficiency (PID)
- Too may infections (i.e. >2 pneumonias, etc) 2. Weird infections (pneumocystis) 3. Infections in weird places (liver, lung abscesses) 4. Early-onset autoimmunity
Describe the major features of the following complement defects: 1. Early (C2, C4) 2. Late (C5-C9) 3. C3
- Sinopulmonary infections, increased susceptibility to S. pneumoniae and H. Influenzae, autoimmune disease (SLE, glomerulonephritis) 2. defective MAC, increase Neisseria infections (increased susceptibility to meningitis, but more likely to survive) 3. Severe pyogenic infections
Workup: complement deficiency
CH50: 0 = deficient, >1 = consumption AH50 for rare alternative pathway defect
Complement deficiency first presents at what life stage?
Any age
Identify the type of immunodeficiency and the initial screening test(s) that should be used: 1. SCID 2. DiGeorge Syndrome (22q11DS) 3. XLA 4. CVID 5. CGD 6. C2, C5-C9 deficiency
In all cases, get CBC with differential first 1. Combined B cell and T cell deficiency -> flow cytometry, TREC 2. T cell deficiency -> FISH, RT-PCR, or chromosome microarray (preferred) 3. Antibody deficiency -> IgG/A/M/E, antibody titers 4. Antibody deficiency -> IgG/A/M/E, antibody titers 5. PMN (neutrophil) defect -> DHR (preferred) or NBT 6. Complement deficiency -> CH50
Describe the etiology of SCID
X-linked is most common (46%). Mutation in the common gamma-chain (gamma-c) of the IL-2 receptor. gamma-c is also a shared component in other IL receptors (IL-4/7/15/21). Effect: T/NK cells not present. B cells present but not functional.
Describe the common clinical manifestations of SCID
Pneumonia (P. jiroveci), otitis media, thrush, intractable diarrhea, failure to thrive
Describe the treatment for SCID
Bone marrow transplant (100% fatal without treatment). Early treatment (<3mo) associated with 95% survival rate.
What is a TREC?
T-cell Receptor Excision Circle (TREC). Measured with qRT-PCR Nonreplicating circular pieces of DNA (cut and spliced out) in naive T-cells generated in the process of making TCRs. TRECs serve as a marker of normal, naive T-cells -> absent in SCID and other forms of T-cell lymphopenia
Describe the etiology of DiGeorge Syndrome (22q11DS)
Microdeletion in chromosome 22q11.2 (usually TBX1 gene), resulting in defects in pharyngeal pouches 1-6.
What are the major clinical features of DiGeorge Syndrome (22q11DS)?
CATCH22: C = cardiac defects A = abnormal facies T = thymic dysplasia C = cleft palate H = hypocalcemia 22 = 22nd chromosome Also: immunodeficiency and developmental delay w/ low IQ T-cell abnormalities (30%) and Antibody deficiency (15%)
Which gene is most commonly associated with DiGeorge Syndrome (22q11DS)?
TBX1
Describe diagnostic testing for DiGeorge Syndrome (22q11DS)
Screening recommended for all infants with significant heart defects or unexplained lymphopenia Chromosome microarray (preferred), FISH (older, 15% false negative), RT-QPCR for TBX1 haploinsufficiency (future)
What is micrognathia
small chin
What are the classic abnormal facies of DGS/22q11DS?
- Micrognathia 2. Low-set ears 3. fish-shaped mouth
XLA (X-Linked Agammaglobulinemia) is due to a defect in which gene?
Btk
Describe the etiology of XLA
X-linked agammaglobulinemia: Due to mutations in Bruton’s Tyrosine Kinase (Btk) -> results in a failure of differentiation of B-cells -> B cells absent, resulting in severe agammaglobulinemia
Describe the major clinical features of XLA
- Onset in infancy or early childhood 2. Recurrent otitis media, sinusitis, pneumonia 3. Bronchiectasis (if not detected early) Infection with encapsulated bacteria (S. pneumoniae, H. Influenzae) and mycoplasma 4. Severe enteroviral infections 5. IgG/A/M/E deficiency
Name the diagnostic labs indicated for detection of XLA
- CBC diff 2. IgG/A/M/E 3. flow cytometry
What is the major cause of death in patients with CVID?
Pulmonary disease (bronchiectasis and interstitial lung disease)
How is CVID diagnosed?
- Decrease IgG (>2 SD below mean) and low IgA and/or IgM 2. flow cytometry to confirm normal B and T cells 3. Exclude secondary immune deficiency in Hx (drugs, lumphoma, protein-losing enteropathy)
Describe the major clinical features of CVID
- Onset at any age 2. Very low IgG and low IgM and/or IgA 2. RTI/GI infections 3. Bad titers with vaccines 4. Neoplasia (including B-cell lymphoma and gastric carcinoma) 5. Autoimmune cytopenias 6. Liver disease (including hepatitis and autoimmune)
If a patient presents with low/absent IgA, but normal IgG and IgM, what is the most likely PID diagnosis?
IgA deficiency
What treatment is contraindicated with IgA deficiency?
IVIG - because non-IgA immunoglobulins are usually normal
What are the major clinical features of IgA deficiency?
(Vast majority of subjets are normal) 1. very low IgA and normal IgG and IgM 2. Increased sinopulmonary and/or GI infections (example: giardia) 3. Increased incidence of atopic disease (coeliac disease and autoimmune disease) 4. False-negative and false-positive diagnostic tests
Why does IgA deficiency cause false results on various serum diagnostic tests?
- False-negative: lack of IgA (IgA Ab to transglutaminase) 2. False-positive: increased incidence of heterophile antibodies (example: pregnancy tests)
What is a heterophile antibody?
An antibody that recognizes an antigen different than the one that induced the original immune response Feature of EBV infections
Normal IgG/A/M/E with normal T-cell function, but an abnormal response to vaccines (especially polysaccharide (PS) antigens) is indicative of what
Specific Antibody Deficiency
Lab evaluation for Ab deficiency: Give the expected findings for each:
- B cell numbers
- IgG
- IgA
- IgM
- Response to immunization
- IgA deficiency
- XLA
- CVID
- Steroid-induced hypogammaglobulinemia
- Specific Ab deficiency
Disorder B cell numbers IgG IgA IgM Response to Immunization IgA deficiency nl nl
<10mg/dl
(very low)
nl nl XLA absent/very low <200mg/dl (low) low/not detectable low/not detectable absent CVID normal to low usually <400 mg/dl (low) low (90%) low (70-80%) decreased/absent Steroid-induced hypogammaglobulinemia usually nl usually >400mg/dl slightly reduced slightly reduced blunted, but not absent Specific Ab deficiency nl nl nl nl decreased
What is the etiology of Chronic Granulomatous Disease (CGD)?
Impaired bactericidal killing due to a functional abscence of respiratory burst in neutrophils and monocytes
Due to a deficiency of NADPH oxidase. Usually X-linked.
What are the major clinical findings of CGD?
- Onset by age 2
- pneumonia
- adenopathy/adenitis/abscesses
- hepatic abscess without obvious source
- sepsis
- osteomyelitis
- infection with catalase+ bacteria
What type of bacteria are usually found with CGD?
Catalase+ bacteria
examples: S. aureus, serratia, salmonella, nocardia, klebsiella, burkholderia
also fungus: candida, aspergillus
How is CGD diagnosed?
Dihydrorhodamine test (DHR)
A liver abscess in an infant or young child without an obvious source is usually what disease?
Chronic Granulomatous Disease (CGD)
Rolling adhesion of leukocytes is mediated by what?
selectins (E-selectin, P-selectin) on the endothelium and sialyl Lewis (CD15) on leukocytes
Tight adhesion is mediated by what?
LFA-1 (CD18/CD11a) with ICAM-1/2
MAC-1 (CD18/CD11b) with ICAM-2
In leukocyte adhesion deficiency, are leukocytes abnormally high or abnormall low?
High
What are the common clinical findings in Leukocyte Adhesion Deficiency 1 (LAD-1)?
- Recurrent pyogenic infections
- Delayed umbilical cord detachment
- leukocytosis
- inability to form pus
What treatment(s) is(are) indicated in LAD-1?
- Aggressive infection treatment
- Bone marrow transplant (severe cases)
What is the etology of LAD-1?
Autosomal deficiency of LFA-1/MAC-1 family of integrins -> leading to low to moderate CD11/CD18 expression
Deficiency in adhesion molecules leads to impaired leukocyte trafficking and margination -> PWNs cannot enter sites of injury/infection to form pus
What is the molecular difference between LAD-1 and LAD-2?
LAD-1: CD18 deficiency
LAD-2: Fucosylation deficiency
What bacteria is especially common in Late Complement (C5-C9) deficiency
Neisseria meningitidis
What is the most common Early Complement Deficiency?
C2
