Immune Deficiencies & Autoimmunity_Clinical Pathology Boards Review
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What is the screening test for CGD? What types of infections do these patients have?
Nitroblue tetrazolium - normal phagocytes can convert yellow dye to blue with normal oxidative function; chronic suppurative from bacteria and fungi that are calatase+ (Staph, Enterobacter, Aspergillus)
What types of infections characterize T-cell function defects and when do they typically present?
viral, parasitic, fungal infections, present in neonatal period
What types of infections characterize neutrophil/phagocytic function defects?
staph, E. coli, S. pneumo, Pseudomonas, and C albicans infxns
What types of infections characterize B-cell function defects and when do they typically present?
Recurrent bacterial sinopulmonary infections (Staph, strep, hemophilus) and recalcitrant Giardia infection, not fungal or viral infections, present 6mos+ due to persistance of maternal Abs
In Burton's agammaglobulinemia, what is the typical presentation? In addition to infections, what diseases do they also have? Mutation?
Recurrent pyogenic infections in male at ~6mos w/ eventual bronchiectasis; high incidence of leukemia/lymphoma and autoimmune d/o; Atk (agamma tyrosine kinase) on Xq22
In Bruton's agammaglobulinemia, what do duodenal, LNs and tonsils histology show? Serology? What is tx?
Giardia and absence of PCs, LN w/out GCs and rudimentary tonsils; low IgG levels (also no CD19+ B-cells in periph blood); IV Ig
What viral infections are Bruton's Agammaglobulinemia pts susceptible to?
Polio, hepatitis, enterovirus (have normal immunity against all other viral infections)
What does serology show in combined variable immunodeficiency (CVI)?
TH1 imbalance causes ↑IL-12 and γ-IFN secretion by TH1 (IL-12 shuts off TH2 cells and IFNγ stimulates macs), and TH2 helps B-cells produce Ab so without it have no class switch → low serum IgG, IgM and IgA
When and how do CVI pts typically present?
2nd and 3rd decades with recurrent upper & lower respiratory infxns (Strep, H. flu, Mycoplasma), intestinal bacterial overgrowth, Giardia with common bronchiectasis
In CVI, what does lymphoid tissue histologically show? Small intestinal bx findings? What is the gene defect in CVI?
Hyperplastic GCs (Bruton's has NO GCs); pronounced follicular hyperplasia with low #s PCs (Bruton's has no PCs); ICOS, AR
What is the most common inherited immunodeficiency dz and what is the prevalence? How do they present clinically?
Selective IgA def with 1:700; recurrent respiratory and GI bacterial infxns with high incidence autoimmunity and can have anaphylaxis with IgA containing blood products
What is a major difference btw transient hypogammaglobulinemia of infancy and Bruton's?
Transient has CD19+ B-cells
What additional Ig def can be seen with IgA def?
IgG2 (transcribed near α region of HC constant region)
Describe the four major hypersensitivity reactions.
- Type I - allergic, IgE mediated (ex. anaphylaxis, asthma)
- II - cytotoxic, Abs produced in response to foreign Ags (ex. drugs) bind to patient's own cells, activating complement (Goodpasture, myasthenia, immune hemolysis)
- III - Ag-Ab complexes deposit and generate immune response (ex. lupus, serum sickness from foreign Ags (ex. horse), post-strep, hsp)
- IV - Delayed, cell-mediated by T4 helper cells (ex. TB test)
What infections are patients susceptible to with IgG2 and IgG4 deficiencies? IgG1 and IgG3? How are these subclass defs dx?
IgG2 and 4 respond to T-independent Ags so def → susceptible to encapsulated infxns; IgG1 and 3 respond to protein Ags so def → susceptible to toxin-producing organisms; test response to pneumococcus or tetanus vaccine
What is the defect in X-linked hyper-IgM deficiency?
Low IgG, A, and E d/to Xq26 mutation encoding CD40L → no binding to CD40 on B-cells → no class switch
What is the major mutation in DiGeorge syndrome and what are phenotypic findings? What drug has been associated? What rare chrom deletion causes DiGeorge II?
Del chrom 22q11.2 (sporadic), failure of 3rd and 4th pharyngeal pouch devt → hypoplastic thymus (T-cell def), parathyroids (hypoCa), and peri-arteriolar lymphatic sheaths in spleen with TOF, abnml facies; accutane; 10p13p14 (same phenotype)
What are serum findings in severe combined immunodeficiency (SCID)? Clinical findings? Two major mutations involved? Minor mutations? Tx?
Low/absent T-cell & Ig with thymic dysplasia; severe immunodef w/ bacterial, viral, fungal, parasitic infxns shortly after birth; 50% IL-2 receptor γ (Xq13) defect and 40% AR adenosine deaminase def (20q13); def JAK3, CD3, or RAG1/RAG2; aggressive anti-microbial +/- BM tx
What is the defect and mutation in LAD-1? Clinical findings? PB findings?
AR, chrom 21q22.3 mutation → poor LFA-1 adhesion molecule formation (CD18) → no neutrophil margination; increased soft tissue infxns and impaired wound healing; marked neutrophilia b/c they can't leave the vessels
For the following complement deficiencies, what are pts susceptible to?
1) C1q, C2, C4 (classic path)
2) C2 & C3
3) C5-9 (MAC complex)
4) C1 esterase inhibitor
- 1) Autoimmune phenomena like lupus
- 2) recurrent GP encapsulated infxns
- 3) recurrent systemic infxns (Neisseria)
- 4) hereditary angioedema w/high urinary histamine and C1 levels during attacks (activation by BK and FXII → vascular permeab → swelling)
What mechanisms lead to loss of self-tolerance/autoimmune disorders?
- 1) Ag sequestration (sperm, lens Ag)
- 2) molecular mimicry (exogenous Ag similar to self like strep, EBV, mycoplasma)
- 3) Tumor autoAgs
- 4) HLA-associated
How does hyper-IgE/Job syndrome present? what is the defect?
Staph infections, eosinophilia, eczema with high IgE and high IgE-specific anti-Staph Abs; granulocyte chemotaxis
What disease shows vacuolization of leukocyte cytoplasm by fat vacuoles?
In ANA screening using Hep2 cells, what diseases cause the following patterns:
- 1) scleroderma
- 2) PBC, autoimmune hepatitis
- 3) mixed connective tissue dz (RNP), 20% scleroderma (Scl-70), 50% Sjogren's (SS-B)
- 4) acute lupus
- 5) Lupus (dsDNA)
- 6) CREST
What mutation is involved in autoimmune lymphoprolif syndrome?
Fas ligand, involved in apoptosis of self-rx T and B cells
What HLA types are associated with the following diseases:
1) Ankylosing spondylitis
2) Multiple sclerosis
3) Rheumatoid arthritis
4) Pemphigus vulgaris
- 1) Ankylosing spondylitis - HLA-B27
- 2) Multiple sclerosis - HLA-DR2
- 3) RA - HLA-DR4
- 4) Pemphigus vulgaris - HLA-DR4
- 5) IDDM - HLA-DR3,4 (HLA-DR2 protective)
What diseases are associated with HLA-DR3?
- Dermatitis Herpetiformis
- Grave's dz and Hashimoto's
What HLA types are associated with the following diseases:
4) Grave's dz
5) 21-OH deficiency
- 1) Narcolepsy - HLA-DR2
- 2) Hashimoto's - HLA-DR3,4, 5
- 3) Celiac - HLA-DQ2, DQ8
- 4) Grave's - HLA-DR3, 8
- 5) 21-OH deficiency - HLA-B47
What is the role of FOXP3 in T-cells? What does a mutation cause?
T-cell regulation; Adult T-cell leukemia
What auto-Ab is dx of lupus? What test result virtually excludes active SLE?
Anti-smith; negative ANA
What ANCA patterns are seen in c-ANCA and p-ANCA?
- c-ANCA: granular with perinuclear accentuation
- p-ANCA (*with ethanol to redistribute MPO): perinuclear immunofluorescence
Identify the autoimmune disorder by the following auto-antibodies:
2) ANA, anti-histone
4) Anti-Jo1 (tRNA synthetase)
5) Anti-glutamic acid decarboxylase
7) Anti-smooth muscle
- 1) Mixed connective tissue dz
- 2) drug-induced lupus
- 3) CREST
- 4) Polymyositis/Dermatomyositis w/ high likelihood of interstitial lung dz
- 5) IDDM
- 6) Scleroderma, Sjogren's
- 7) Autoimmune hepatitis
ANA studies use the Crithidia lucilae worm. What structure must fluoresce for a + result?
What 3 drugs are associated with drug-induced SLE?
procainamide, hydralazine, isoniazid
What infection is associated with the onset of ankylosing spondylitis?
What infection is associated with IDDM devt?
Coxsackie B virus
What anti-hypertensive drug can lead to autoimmune hemolytic anemia?
Aldomet (Methyl dopa)
What is rheumatoid factor? What other marker is more sensitive and specific for RA?
IgM (usu) against Fc portion of other IgG, poly or monoclonal, can form cryoglobulin, may be in synovium or cartilage, forms immune complexes; anti-cyclic citrullinated peptide
What is the mechanism of autoimmunity in SLE vs. scleroderma?
- Oposite mechanisms:
- SLE: defective T-cell suppression
- Scleroderma: Helper T-cell activation and B-cell activation
All of the following are autoAbs are in polymyositis except:
C) Anti-tRNA synthetase
- *tRNA synthetase = Anti-Jo1
A patient p/w proximal muscle weakness, ↑CK, characteristic EMG findings. She has a heliotrope rash and Gottron papules. Dx? What Abs are likely present?
Dermatomyositis; Anti-Jo1 and Anti-Mi-2 (good prognosis)
Among the inflammatory myopathies, which Ab has a high freq of cardiac involvement? pulmonary fibrosis?
Anti-SRP; anti-synthetases (anti-Jo1 and anti-PL-7)
What inflammatory myopathy shows inclusion bodies on muscle bx? Frequently has anti-SRP Abs? Has elevated muscle enzymes (CK, aldolase, etc.) levels?
Inclusion body myositis; polymoyositis; polymyositis
What Ab is associated with Crohn's dz?
Anti-saccharomyces ceriviseae (ASCA)
How can you tell if perinuclear ANCA staining is due to p-ANCA, atypical ANCA, or ANA? What if the staining becomes negative?
Run specimen on formalin-fixed neutrophils, if the staining becomes cytoplasmic, it's p-ANCA; it's atypical ANCA or ANA (can run on Hep2 cells to r/o ANA)
Which ANCA is fluorescing in each picture?
- Top: c-ANCA (proteinase 3)
- MIddle: p-ANCA (MPO)
- Bottom: atypical ANCA
Which Sjogren Ab is mostly confined to primary dz?
All of the following are IgG4-associated diseases except:
A) Reidel's thyroiditis
B) Mixed connective tissue dz
C) Autoimmune pancreatitis
D) Inflammatory pseudotumor
E) Mikulicz's syndrome
LATS/long-acting thyroid stimulating Abs are seen in 100% of pts with what dz? Are they seen in other thyroid-related diseases?
What is the age of onset and what gender is more common in primary biliary cirrhosis? What serum Ig is elevated? What other diseases are associated with PBC?
30-35yo females; IgM polyclonal; CREST & primary sjogren's
What is the age of onset and what gender is more common in autoimmune hepatitis? What serum Ig is elevated? What specific set of antibodies are associated?
- adolescence and young adulthood, females; IgG; ANA, anti-SMA and LKM1 Ab in prox tubules (against CYP2D6)
- Also sometimes anti-soluble liver Ag (SLA/LP)
In celiac, what antibodies are the best to dx? What type of Anti-gliadin Ig is sensitive and which is specific? What three diseases are strongly associated with celiac? What absorption test is useful for dx?
Anti-tissue transglutaminase (IgA sensitive but is not specific due to high incidence in chronic liver dz) & anti-endomysial Abs / OR newer studies say IgA anti-TTG and IgA anti-deamidated Gliadin (use IgG if pt IgA deficient); IgG sensitive, IgA specific; DM, IgA deficiency, and cystic fibrosis; D-xylose absorption test
What is tissue transglutaminase?
enzyme that deamidates gliadin
What antibodies are associated w/myasthenia gravis?
Anti-AchR, anti-skeletal muscle cmpts (ryanodine receptor and titin) in late-onset and thymoma-associated dz, and MuSK Abs in anti-AchR-negative pts (younger females w/freq bulbar manifestations)
Clinical sxs of myasthenia gravis? 10% of pts also have what associated pathologic finding?
Ptosis, diplopia, fatigueable muscle weakness with EMG findings (progressive decrement in muscle AP and +Tensilon test w/ dramatic response to cholinesterase inhib); thymoma or thymic hyperplasia
What is the Lambert-Eaton variant of myasthenia gravis?
Prox muscle weakness, >40yo, other autoimmune dz or small cell CA
What is the role of C1 esterase inhibitor?
Inhibits complement activation to prevent spontaneous activation
Which complement factors are important in chemotaxis and mast cell degranulation (anaphylatoxins)?
C3a and C5a
What forms are in C3 convertase? What does the complex do?
C3bBb and C4bC2a; cleaves C3 to C3a and C3b
What is the role of C3b?
Binds microbes to aid in opsonization and cleaves C5 → C5a and C5b
What are the opsonization molecules in complement?
Mannose binding lectin, C3b and C4b
Which Igs activate the complement pathway? Which one is better?
IgM and IgG; IgM b/c you need several IgGs to activate while only one IgM is req'd
Which IgG subclasses easily cross the placenta? Which IgG is most abundant in serum? Which IgG does not activate complement?
IgG1, 2, and 4; IgG1; IgG4
What is the most common cause of mortality in SLE pregnancy? What else do they have an increased risk of?
Pulmonary hemorrhage from lupus pneumonitis; pregnancy-induced HTN
What types of injuries/conditions cause elevated aldolase?
- muscle injury like Duchenne's muscular dystrophy, polymyositis, dermatomyositis
- *Not elevated in neurogenic atrophy like MS, myasthenia gravis
What is the other name for Anti-Scl70 in scleroderma?
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