Rheumatology: Pathology - Autoimmunity and immunodeficiency Flashcards
1
Q
Antigens involved and clinicopathologic manifestations of SLE
A
Ag: DNA, nucleoproteins, others
Manifestations: nephritis, arthritis, vasculitis
2
Q
Antigens involved and clinicopathologic manifestations of polyarteritis nodosa
A
Ag: HBsAg (in some cases)
Manifestations: vasculitis
3
Q
Antigens involved and clinicopathologic manifestations of PSGN
A
Ag: streptococcal cell wall Ag (may “plant” in GBM)
Manifestations: nephritis
4
Q
Antigens involved and clinicopathologic manifestations of acute glomerulonephritis
A
Ag: bacterial Ag (e.g. treponema), parasite Ag (e.g. malaria, schistocytes), tumour Ag
Manifestations: nephritis
5
Q
Antigens involved and clinicopathologic manifestations of reactive arthritis
A
Ag: bacterial Ag (e.g. Yersinnia)
Manifestations: acute arthritis
6
Q
Antigens involved and clinicopathologic manifestations of Arthus reaction
A
Ag: various foreign proteins
Manifestations: cutaneous vasculitis
7
Q
Antigens involved and clinicopathologic manifestations of serum sickness
A
Ag: various proteins (e.g. foreign serum of anti-thymocyte globulin)
Manifestations: arthritis, vasculitis, nephritis
8
Q
What is tolerance?
A
Phenomenon of unresponsiveness to an antigen as a result of exposure of lymphocytes to that antigen
9
Q
What is central vs peripheral tolerance?
A
Central: immature self-reactive T and B cells that recognise self-antigens during maturation are destroyed
Peripheral: inactivation or destruction of self-reactive lymphocytes in the periphery (via anergy, suppression by regulatory T cells, or activation-induced cell death)
10
Q
What is the sex preponderance of SLE?
A
More common in women than men (9:1)
11
Q
What autoantibodies are seen in SLE? Which are sensitive and which are specific?
A
Anti-nuclear antibodies (sensitive but not specific)
Anti-dsDNA Ab (specific)
Anti-Smith Ag Ab (specific)
Ab directed against blood elements (RBCs, platelets, leukocytes)
Antiphospholipid Ab (40-50%)
12
Q
What are LE cells?
A
Seen in SLE
Formed when ANAs react with nuclei of damaged cells (cannot penetrate intact cells), causing nuclei to lose chromatin and become homogenous LE (haematoxylin) bodies which are then phagocytosed to produce LE cells
13
Q
What autoimmune disease can produce a false positive to the VDRL test for syphilis and why?
A
SLE, due to auto-Ab binding cardiolipin
14
Q
What is lupus anticoagulant and what is its clinical significance in SLE?
A
Antiphospholipid antibody that has anticoagulant effects in vitro (prolongs APTT) but in vivo has a procoagulant effect
Confers increased risk of recurrent thrombosis, miscarriage, MI, CVA (termed “secondary antiphospholipid antibody syndrome” in SLE)
15
Q
Describe the aetiology and pathogenesis of SLE
A
Genetic predisposition
Exogenous factors (e.g. UV exposure, oestrogens, certain drugs including hydralazine and procainamide)
16
Q
What type of hypersensitivity reaction predominates in SLE?
A
Type III (immune complex mediated)
17
Q
Describe the morphologic findings of SLE
A
Acute necrotising vasculitis involving capillaries, small arteries, and arterioles may be present in any tissue (highly variable)
18
Q
Eight organ systems commonly affected in SLE
A
- Kidney
- Skin
- Joints
- CNS (neuropsychiatric symptoms)
- Serositis (including pericarditis)
- Heart
- Spleen
- Lungs
19
Q
Describe the five morphologic stages of lupus nephritis
A
- Class I: normal by light/electron/fluorescence microscopy (rare)
- Class II: mesangial lupus GN (20%; minimal haematuria or proteinuria)
- Class III: focal proliferative GN (20%; recurrent haematuria, moderate proteinuria, occasionally mild renal insufficiency)
- Class IV: diffuse proliferative GN (40-50%, most severe form with worst prognosis; haematuria, proteinuria which may be in nephrotic range, HTN, decreased GFR)
- Class V: membranous GN (15% severe proteinuria or nephrotic syndrome)
20
Q
Describe the common cutaneous symptoms of lupus
A
Classically malar erythema with variable cutaneous lesions elsewhere, and exacerbated by sunlight
21
Q
What joint changes occur in SLE and how does this compare with RA?
A
Nonerosive synovitis with little deformity (unlike RA)
22
Q
Give two examples of cardiovascular manifestations of SLE
A
Verrucous (Libman-Sacks) endocarditis
Valvular abnormalities
23
Q
What three changes are seen in the spleen with SLE?
A
- Splenomegaly
- Capsular thickening
- Follicular hyperplasia
24
Q
What lung manifestations of SLE are there?
A
- Pleuritis
- Pleural effusions
- Interstitial pneumonitis
- Diffuse fibrosing alveolitis
25
Describe the typical clinical course of SLE
Sometimes minimal symptoms with spontaneous remission
More commonly relapsing-remitting
Ten-year survival ~80%
26
What are the most common causes of death related to SLE?
Renal failure
Intercurrent infection
27
What is primary vs secondary immunodeficiency?
Primary: usually hereditary, typically manifesting between 6mo and 2yrs of age due to loss of maternal antibody protection
Secondary: acquired, results from altered immune function
28
Seven broad causes of secondary immunodeficiency
1. Infections
2. Malnutrition
3. Aging
4. Immunosuppression
5. Irradiation
6. Chemotherapy
7. Autoimmunity
29
List five examples of primary immunodeficiencies and give a brief explanation of the clinical presentation seen with each
1. X-linked agammaglobulinaemia: recurrent bacterial respiratory tract infections
2. SCID: severe recurrent infections, with a wide variety of pathogens
3. Common variable immunodeficiency: hypogammaglobulinaemia, similar clinical presentation to XLA
4. Isolated IgA deficiency: common, may be asymptomatic
5. Hyper-IgM syndrome: deficiency of IgG, IgA and IgE results in recurrent pyogenic infection
30
Which primary immunodeficiency may also be acquired and how?
Isolated IgA deficiency may be acquired via toxoplasmosis or measles, amongst other infections
31
What is the most common pattern of inheritance of common variable immunodeficiency?
X-linked
32
What is AIDS?
Disease caused by HIV and characterised by profound suppression of T cell-mediated immunity, resulting in:
- Opportunistic infection
- Secondary neoplasms
- Neurologic manifestations
33
Five at-risk groups for AIDS (and their relative proportions)
1. Men who have sex with men: >50%
2. IVDU: 20%
3. Heterosexual contacts of other high-risk groups (predominantly IVDUs): 10%
4. Haemophiliacs (especially those who received F VIII and F IX prior to 1985): 0.5%
5. Other blood product recipients: 1%
34
Describe the three modes of transmission of HIV. Which is most common?
1. Sexual transmission (predominant mode of transmission, with heterosexual transmission being most important globally)
2. Parenteral transmission
3. Vertical transmission (via transplacental spread, birth canal during delivery, or breastfeeding)
35
How can risk of vertical transmission be virtually eliminated in HIV-positive mothers?
With antiretroviral therapy
36
What is the risk of HIV seroconversion with needlestick injury in the healthcare setting? How is this changed by post-exposure prophylaxis?
0.3%, further reduced 8-fold with PEP
37
What is the effect of co-existing STI on risk of HIV transmission through sexual contact?
Risk increased with any STI but especially those associated with genital ulceration
38
What type of virus is HIV-1?
Human type C retrovirus belonging to lentivirus family
39
Where is HIV-2 found?
Predominantly in West Africa and India
40
Describe the structure of HIV-1
Spherical virus with electron-dense cone-shaped core, surrounded by matrix protein p17 layered beneath a lipid envelope derived from host cell membrane
Two glycoproteins on viral envelope: gp120 and gp41
41
Describe the 4 contents of the HIV-1 viral core
1. Major capsid p24
2. Nucleocapsid p7/p9
3. Two copies of genomic RNA
4. Three viral enzymes (protease, reverse transcriptase, integrase)
42
Which HIV viral component is typically used for diagnostic ELISA?
Major capsid p24 (most readily detected viral Ag)
43
How does HIV infect CD4+ T cells?
- CD4 Ag is the high-affinity receptor for the gp120 protein on HIV
- Virus must also bind co-receptors CCR5 and CXCR4 on host cell
- After binding, virus is internalised and genome undergoes reverse transcription, with resultant proviral DNA intergrated into host genome
- Subsequent transcription/translation and viral propagation relies on T cell activation (antigenic stimulation: either by HIV or some other infection), and if this does not occur then the infection enters a latent stage
44
What sequence of events occurs during the acute early phase of HIV infection?
- Infection and subsequent death of CD4+ T cells in mucosal lymphoid tissues leads to T cell depletion (in early disease there is selective loss of memory T cells)
- Dendritic cells capture virus and migrate to lymph nodes where they present and pass on the virus to CD4+ T cells
- Viraemia results, with dissemination of infected cells throughout the body and further infection of CD4+ T cells, macrophages and dendritic cells in peripheral lymphoid tissues
45
What sequence of events occurs during the seroconversion phase of acute HIV infection? How do patients present in this phase?
- Within 3-7 weeks of exposure, individual amounts an immune response and develops HIV-specific CD8+ cytotoxic T cells
- CD8+ T cells gain partial control of infection and viraemia drops to low but detectable levels by ~12 weeks post exposure
- During this phase patients may present with acute viral syndrome with flu-like symptoms
46
What is the utility of monitoring CD4+ counts in HIV infection?
Guides when to commence antiretrovirals
46
What is the utility of measuring viral load at the end of the acute phase of HIV infection?
Provides an indication of HIV progression
47
What are the two phases of chronic HIV infection?
1. Clinical latency
2. AIDS
48
What sequence of events occurs during the clinical latency phase of chronic HIV infection? How do patients present? How long does this phase typically last before progression to AIDS?
- Lymph nodes and spleen are sites of continuous HIV infection and cell destruction
- CD4+ cell count slowly declines
- Patients may be either asymptomatic or experience minor opportunistic infections (e.g. candidiasis, HZV)
- Typically lasts 7-10 years
49
What sequence of events occurs at onset of AIDS? How do patients present?
- Breakdown of host defence, dramatic increase in plasma virus, and severe life-threatening disease
- Patients present with long-lasting fever, fatigue, weight loss, and diarrhoea
- Subsequently develop AIDS-defining illnesses after a variable period
50
Describe the phases of acute and chronic HIV infection
1. Acute early infection
2. Seroconversion
3. Clinical latency period of chronic infection
4. AIDS
51
At what CD4+ count is AIDS diagnosed in a HIV+ patient (regardless of presence or absence of symptoms)?
<200 cells/ul
52
What immune cells apart from T cells are infected by HIV and what is their role in the pathogenesis of disease?
1. Monocytes and macrophages: refractory to cytopathic effects of HIV and so act as important reservoirs of disease and transporters (including to CNS - role in pathogenesis of neurologic manifestations)
2. Follicular dendritic cells: also important viral reservoir
53
What happens to B cells during HIV infection?
There is paradoxical activation, but with inability to mount effective immune response to new antigen (likely due to lack of CD4+ T helper cells and/or intrinsic B cell defects)
54
Five major abnormalities of immune function seen in HIV
1. Lymphopaenia: selective CD4+ T cell loss with inversion of CD4:CD8 ratio
2. Decreased T-cell function in vivo
3. Altered T-cell function in vitro
4. Polyclonal B-cell activation
5. Altered monocyte or macrophage functions
55
Describe four features of the decreased T cell function in vivo observed in HIV
1. Preferential loss of activated and memory T cells
2. Decreased delayed-type hypersensitivity
3. Susceptibility to opportunistic infection
4. Susceptibility to neoplasms
56
Describe four features of the altered T cell function in vitro observed in HIV
1. Decreased proliferative response to mitogens, alloantigens, and soluble antigens
2. Decreased cytotoxicity
3. Decreased helper cell function for B-cell antibody production
4. IL-2 and IFN-y production
57
Describe three features of the polyclonal B cell activation observed in HIV
1. Hypergammaglobulinaemia and circulating immune complexes
2. Inability to mount de novo antibody response to new antigen
3. Poor responses to normal B cell activation signals in vitro
58
Describe three features of the altered monocyte or macrophage functions observed in HIV
1. Decreased chemotaxis and phagocytosis
2. Decreased class II HLA expression
3. Decreased capacity to present Ag to T cells
59
Four clinical features of AIDS
1. Opportunistic infections
2. Pyogenic bacterial infections (reflecting altered humoral immunity)
3. Tumours
4. CNS disease
60
In what % of untreated AIDS patients does PJP occur?
15-30%
61
Give 10 examples of common opportunistic infections seen in AIDS
1. Pneumocystis jiroveci
2. Candida
3. CMV
4. Atypical and typical mycobacteria
5. Cryptococcus neoformans
6. Toxoplasma gondii
7. Cryptosporidium
8. HSV
9. Papovaviruses
10. Histoplasma capsulatum
62
Give four examples of common neoplasms seen in AIDS. Which is most common?
1. Kaposi sarcoma (most common; associated with HHV-8)
2. Aggressive B-cell NHL (associated with EBV)
3. Cervical cancer
4. Anal cancer in men
63
What is Kaposi sarcoma?
A vascular tumour composed of spindle cells that form vascular channels, with a strong association with HHV-8
64
What % of patients with AIDS develop clinical neurologic manifestations?
40-60%
65
Two protozoal/helminthic AIDS-defining opportunistic infections
1. Cryptosporidiosis or isosporidiosis (enteritis)
2. Toxoplasmosis (pneumonia or CNS infection)
66
Five fungal AIDS-defining opportunistic infections
1. Pneumocystosis (pneumonia or disseminated infection)
2. Candidiasis (oseophageal, tracheal, or pulmonary)
3. Cryptococcosis (CNS infection)
4. Coccidioidomycosis (disseminated)
5. Histoplasmosis (disseminated)
67
Three bacterial AIDS-defining opportunistic infections
1. Mycobacteriosis ("atypical" - disseminated or extrapulmonary; M. tuberculosis - pulmonary or extrapulmonary)
2. Nocardiosis (pneumonia, meningitis, disseminated)
3. Salmonella (disseminated)
68
Four viral AIDS-defining opportunistic infections
1. CMV (pulmonary, intestinal, retinitis, CNS infections)
2. HSV (localised or disseminated)
3. VZV (localised or disseminated)
4. Progressive multifocal leukoencephalopathy (caused by JC virus)
69
Four AIDS-defining neoplasms
1. Kaposi sarcoma
2. B-cell NHL
3. Primary lymphoma of brain
4. Invasive cancer of uterine cervix
70
What is amyloid?
Pathologic proteinaceous substance deposited in extracellular space in various tissues and organs of the body in a wide variety of clinical settings
71
What is amyloidosis?
Refers to a group of conditions characterised by the deposition of amyloid
72
Describe the structure of amyloid. How is it produced
Not a structurally homogenous protein although always looks the same (forms characteristic fibrils): accumulates due to the excess synthesis or impaired catabolism of proteins, which then aggregate into an insoluble conformation and are deposited extracellularly
73
What are the three common types of amyloid and how is each produced? Which disease state is each typically found in?
1. AL (amyloid light chain): Ig light chains derived from plasma cells, associated with B cell dyscrasias (e.g. MM)
2. AA (amyloid associated): non-Ig-related, synthesised in liver from SAA and elevated in chronic inflammatory states (most commonly RA)
3. AB2 (beta-2 amyloid): found in Alzheimers disease
74
What other two proteins are associated with amyloid?
1. Transthyretin: normal serum protein that binds and transports thyroxine and retinol, but in mutant form deposits as amyloid (i.e. in familial amyloid polyneuropathy)
2. B2-microglobulin: smaller non-polymorphic peptide component of MHC I (normal serum protein), deposited in amyloidosis associated with longterm haemodialysis
75
Five types of systemic amyloidosis
1. Primary amyloidosis
2. Secondary (reactive) amyloidosis
3. Haemodialysis-related
4. Heredofamilial amyloidosis
5. Senile systemic amyloidosis
76
Two types of localised amyloidosis and a brief description of each (including most commonly affected tissues)
1. Nodular (tumour-forming) deposits: often AL protein with associated plasma cell infiltrates, and most often found in lung, larynx, skin, bladder, tongue and periorbitally
2. Endocrine amyloid: deposition in variety of endocrine tumours including thyroid medullary carcinoma, pancreatic islet tumours, phaeochromocytoma, undifferentiated gastric carcinoma, and in islets of Langerhans in T2DM
77
What type of amyloid is deposited in primary amyloidosis and how is it produced? What tissues are typically involved?
AL type amyloid caused by B-cell dyscrasias
Composed of M spike protein and Bence-Jones protein synthesised by tumorous plasma cells (although not all MM patients with these proteins in their urine will develop amyloidosis)
Typically involves heart, GIT, peripheral nerves, skin, tongue
78
What type of amyloid is deposited in reactive amyloidosis and what disease states are implicated? What tissues are typically involved?
AA type amyloid, associated with chronic inflammatory states (e.g. RA most commonly, IBD, scleroderma, dermatomyositis, bronchiectasis, chronic osteomyelitis)
Typically involves kidneys, liver, spleen, lymph nodes, adrenals, thyroid
79
Describe haemodialysis-related amyloidosis. How does it occur and how can it present?
B2 microglobulin is not filtered by normal haemodialysis and accumulates
Affects over half of those on longterm (>20yrs) dialysis
May present with carpal tunnel
80
Give two examples of heredofamilial amyloidoses
1. Familial mediterranean fever
2. Familial amyloidotic polyneuropathies
81
Where does amyloid predominantly deposit in senile systemic amyloidosis? How does this present clinically?
Usually in heart
Can cause restrictive cardiomyopathy and arrhythmia
82
Describe the macroscopic and microscopic morphology of amyloidosis with respect to their staining patterns
Macroscopic: affected tissues stain blue-violet with iodine and dilute sulfuric acid
Microscopic: amyloid is amorphous, acellular, hyaline and eosinophilic; special stain Congo red turns it a salmon-pink colour with characteristic yellow-green birefringence present under polarised light
