Autoimmune and autoinflammatory conditions Flashcards

Question

Clinical features of ALPS **Autoimmune lymphoproliferative syndrome**

Answer 1

* High lymphocyte count: * Double negative CD4-ve and CD8-ve T cells * Large spleen * large lymph node * Autoimmune diseases: * commonly autoimmune cytopaenias * Lymphoma- high risk

Answer 2

* Crohns * UC * osteoarthritis * Takayasu arteritis * Giant cell arteritis

Answer 3

Multiple genes affected: * Mutations in the genes encoding proteins involved in pathways associated with **innate immune cell function** Affect the innate immune system * lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage HLA associations are less strong Generally not characterised by the presence of autoantibodies

Answer 4

Ankylosing spondylitis Psoriatic arthritis Bechets BAP

Answer 5

- can affect innate and adaptive immune response * Mutations in genes encoding proteins involved in pathways associated with ***_innate immune cell function AND adaptive immune cell function_*** - HLA associations may be present - usually NO AUTOANTIBODIES - usually autoimmune disease **\*\*H for HLA, H for halfway. between autoimmune and autoinflammatory- there are some HLA associations in mixed pattern diseases\*\***

Answer 6

1. HLA-B27 - most common mutation * 50% of the heritability of AS comes down to **HLA-B27 – associated with developing ankylosing spondylitis** 2. IL23 Receptor: 3. IL receptor type 2

Answer 7

* tends to occur at **specific sites** - at ENTHESES - where tendon/ligament inserts into bone * localised pattern - eg sacroiliac joints * can get bone formation eg bamboo spine feature of localisation is characteristic of auto-inflammatory disease **Clinical presentation** * Low back pain and stiffness * Enthesitis i.e. plantar fasciitis, Achilles tendonitis * Large joint arthritis * Sacroiliitis **Treatment** * first line: NSAIDS * immunosuppression if not responding to NSAIDS - aniti TNF alpha, anti IL17

Answer 8

* genetic polymorphisms * **Mutations in genes encoding proteins** involved with pathways associated with **_adaptive immune cell function_****__** * loss of tolerance \>\> development of immune reacivity towards self antigens * generation of autoantibodies * **HLA associations are very common** * as HLA is involved in presentation of antigen by T cells to B cells

Answer 9

genetic polymorphisms (HLA polymorphisms), that lead to loss of tolerance and autoreactive B cells, T cells and autoantibodies "DRS GG" diabetes rheuamtoid sle goodpastures graves

Answer 10

HLA DR15 HLA-DR2 \*\*these are actually the same\*\*

Answer 11

HLA-DR3 grave--\>serious--\>odd number--\>HLA DR 3

Answer 12

HLA-DR3 \*\*SLE has 3 letters\*\*

Answer 13

HLA DR3 or HLA DR 4

Answer 14

1. CTLA4 \>\>\> **inappropriate T cell activation**. 2. PTPN 22 \>\> failure to control T cell activation \>\>\> more reactive T cells \>\> autoimmune disease These are negative regulators of T cell activity Mutations in these genes lead to overactive T cells/inappropriately activated T cells --\> autoimmunity

Answer 15

Classifies immunopathology based on whether it's predominantly T cell or antibody mediated * **Type I:** immediate hypersensitivity which is IgE mediated (this is allergy) * **Rarely directed at self-antigens so rarely autoimmune** * **Type II:** antibody reacts with cellular antigen * **Can be part of autoimmune reaction** * **Antibody mediated** * **Type III:** antibody reacts with soluble antigen to form an immune complex (which circulate) * **Antibody reacting with soluble antigen forming immune complex and inflammation** **** * **Type IV:** delayed-type hypersensitivity, T cell mediated response

Answer 16

Type 1 hypersensiivity \*both\*

Answer 17

Type 1 hypersensiivity

Answer 18

Type 2 hypersensitivity

Answer 19

Type IV T!DM- 4 letters; type 4

Answer 20

Type 2 is very often autoimmune Type 3 and 4 are sometimes autoimmune

Answer 21

Th17 cells attack myelin basic protein and proteolipid protein in brain

Answer 22

* Nonspecific neurological symptoms * → optic neuritis, weakness, blurred vision * worse vision after bath = Uhthoff's phenomenon * tiredness * weight loss

Answer 23

Oligoclonal bands of IgG in CSF

Answer 24

Natalizumab - prevents lymphocyte migration into CNS

Answer 25

1. organ specific * Graves * Hashimotos * Diabetes * Pernicious anaemia * Myasthaenia gravis * Goodpasture's disease 2. organ non-specific * Rheumatoid arthritis * SLE * Sjogren's * systemic sclerosis * dermato/polymyositis * ANCA associated vasculitis

Answer 26

type 2 hypersensitivity signs and symptoms of hyperthyroidisim * **IgG antibodies which stimulate the TSH Receptor** * This stimulates the receptor \>\> **excess production of thyroxine**

Answer 27

IgG antibodies that stimulate TSH receptor Type II hypersensitivity reaction - Antibody-driven Autoimmune Disease

Answer 28

Hypothyroidism: **Lethargic, dry skin and hair, constipation, cold intolerance** * Result in a goitre \>\> **enlarged thyroid infiltrated by _T and B cells_**

Answer 29

Type II and Type IV

Answer 30

* **Anti Thyroid Peroxidase** antibodies- **MORE SPECIFIC \>\>** * *Presence correlates with _thyroid damage_ and _lymphocyte infiltration_* * **Anti thyroglobuin antibodies** - could be present due to consequence of thyroid damage rather than pathogenic - destruction of thyroid gland cells - infiltration of thyroid gland by T and B cells --\> GOITRE

Answer 31

Type IV * The **antigen is within the pancreatic** **beta cells** * **CD8 mediated destruction of beta cells**

Answer 32

* MHC I on beta cells presents self peptide to CD8+ T cells * self-peptide found in Beta cells: **GAD, Islet cell antigen 2** * CD8+ T cells attack Beta cells --\> can't produce insulin * T cell clones have specificity for _islet antigens_

Answer 33

**Anti-GAD + Anti- islet cell, others include:** * Anti-insulin * Anti-IA2 NOTE: individuals with 3-4 of the above are highly likely to develop T1DM \*presence of autoantibodies predates the onset of symptoms by a lot \*currently has no role in diagnosis \>\> based on clinical manifestation + glucose levels

Answer 34

Anti intrinisc factor-- seems like this is more speciifc (from haem lecture) Anti parietal cell * antibodies against **intrinsic factor \>\>\>\>** failure of absorption of vitamin B12.

Answer 35

* Vit B12 deficiency * Macrocytic anaemia- Raised MCV * hypersegmented neutrophils clinical features: **Tired,pale, mild numbness of feet, macrocytic anaemia, _vitamin B12 deficiency, normal folate_** * Neurological features * subacute combined degeneration of the spinal cord * peripheral neuropathy * optic neuropathy

Answer 36

* affects posterior and lateral columns- degeneration - sensory function * bilateral weakness * bilateral paraesthesia * progressive ataxia * babinski and rhomberg's test positive Reversible with B12 **peripheral neuropathy + optic neuropathy**

Answer 37

if antibodies are positive need B12 injections no point giving PO supplements, need to give injections: **_Need parenteral vitamin B12_**

Answer 38

* antibodies against nAChr--\> failure of depolarisation \>\>\> **do NOT get muscle action potential** which results in muscle weakness * results in clinical features: FLUCTUATING MUSCLE WEAKNESS * drooping eyelids - Ptsosis * repetitive movements --\> fatiguing * weakness - worse at the end of the day

Answer 39

MG: ptosis (drooping eyelids) Dermatomyositis: ocular muscles are spared

Answer 40

* AChr antibody - 75% of patients * **tensilon test- definitive diagnosis** * **administering a very short-acting anticholinesterase** (edrophonium bromide) \>\>\> **RAPID IMPROVEMENT IN SYMPTOMS**.

Answer 41

Type 2 hypersensitiivty

Answer 42

Anti-GBM antibody * **basement membrane** **collagen type IV** which is present in the **lungs- haemorrhage** and **kidneys- glomerulonephritis**

Answer 43

- lung disease: widespread crackles, widespread shadowing on x ray, pulmonary haemorrhage - kidney disease: nephritic syndrome: oedema, proteinuria, haemturia, hypertension

Answer 44

1. anti GBM antibodies - smooth linear deposition of antibodies along the basement membrane - detected using fluorescein conjugated anti-human immunoglobulin 2. **crescenteric nephritis** on kidney biopsy

Answer 45

* Genetic predisposition: * HLA DR4 (DRB1 0401, 0404, 0405) * HLA DR1 (DRB1 0101) * **PTPN22** * Polymorphisms affecting TNF, IL-1, IL-6 and IL-1 * PAD2 and PAD4 polymorphisms Basically there is a genetic predispositon to increased citrulinsation (removal of arginine and conversion to citruline) * _Environmental Factors_ * Smoking \>\> increased citrulinsation * Gum infection with Porphyromonas gingivalis \>\>\> only bacterium known to express PAD, thereby promoting citrullination

Answer 46

**1. Anti CCP antibodies** are diagnostic: **_- antibodies against citrullinated peptide_** * **Anti-cyclic Citrullinated Peptide Antibodies\** * Bind to **peptides in which arginine has been converted to citrulline by PAD** 2. rheumatoid factor - outdated - An antibody directed against the **Fc region of human IgG**

Answer 47

PAD- _Peptidyl Arginine Deiminases (PAD2 and 4)_ **Converts arginine to citruline** This is what **antibodies in rheumatoid arthritis bind to** Anything that increases cirtullination increases the risk of rheumatoid arthritis i..e smoking, gum infections

Answer 48

1. Type II * **antibodies bind to citrullinated peptide** * immune complexes activate classical pathway of complement * also activates macrophages and NK cells 2. Type III * immune complexes deposit in areas \>\> leads to compliment activation 3. Type IV * **APCs will present peptides to CD4 T cells \>\>\> production of IFN gamma and IL-17** -- \> activates macrophages and and fibroblasts \>\>\> production of: * MMPs * IL-1 * TNFa

Answer 49

the synovium becomes very inflamed forming a **_pannus_** Type of extra growth in joint that causes pain, swelling and damage invades the articular cartilage and adjacent bone + **increase in synovial fluid volume**

Answer 50

High CH50 As complement factors are activated

Answer 51

HLA-DR2 and HLA DR 15

Answer 52

SLE Systemic sclerosis Dermatomyositis

Answer 53

Jaccoud Arthropathy - correctible joint deformity

Answer 54

1. abnormalities clearing apoptotic cells: **Lots of dying cells which are not cleared and lots nuclear debris** 2. abmormalities in cellular activation: **Increased B and T cell activations \>\> B cell hyperactivity** and **loss of tolerance** occurs **Combination of nuclear debris and hyperactive immune cells = development of antibodies against nuclear proteins**

Answer 55

Type 3: * Antibodies bind to antigens forming **immune complexes** Immune complexes can deposit in s**_mall blood vessels leading to skin, joints, kidneys etc._** They activ**ate complement via classical pathway** + stimulate cells that express Fc (macrophages) and complement receptors \>\>\>\> **_Cascade of inflammation_**

Answer 56

Type 2: antibody mediated. Linear deposition of antibodies at specific sites e.g. Goodpasture's syndrome - anti GBM antibodies * GP: get antibody binding in a linear fashion at the basement membrane – **evenly distribute**d. As antibodies a_gainst cellular antigens_ Type 3: immune complex mediated. Immune complexes deposit in a granular pattern e.g. lupus nephritis :**lumpy-bumpy distribution of antibody formation**

Answer 57

**_Higher the dilution, higher the antibody level_** eg 1:340 means higher antibody level than 1:10 It is represented as the greatest dilution at which the antibody can be detected. So if it can be detected at a very high dilution then the concentration must be high. **HIGH titres are associated with SEVERE disease \>\>** _Titre is important in disease monitoring_

Answer 58

1. anti dsDNA 2. **components within the nucleus**: ENA: - anti ribonucleoprotein- anti-ro, anti-la, anti-sm, anti-u1rnp - SCL 70- anti topoisomerase - anti centromere 3. cytoplasmic t-rna synthetase (Jo1)

Answer 59

1. homogenous: anti ds-DNA \>\> HIGH titres are associated with SEVERE disease \>\> **Titre is important in disease monitoring** 2. speckled: anti- ENA: extractable nuclear antigens (ENA) \>\> Specificity is for some **_ribonucleoproteins_** (e.g. Ro, La, Sm, UR1NP \>\>\> Titres are **NOT helpful in monitoring disease activity** – so only need to measure once to see if they are or not

Answer 60

anti DS DNA is useful for monitoring SLE activity but anti ENA is not useful

Answer 61

* immune complex formation triggers classical pathway of complement activation by exposing the binding site for C1q * this leads to consumption of C3 and C4 if constantly consumed * C4 is consumed before C3 * this can be used to monitor disease activity/severity * if both are low - VERY severe disease * **Quantification of C3 and C4** acts as a surrogate marker for _DISEASE ACTIVITY_ * NOTE: **we measure UNACTIVATED complement proteins rather than activated ones**

Answer 62

CRP: normal ESR: raised

Answer 63

anti phospholipid Ab

Answer 64

**lupus anticoagulant:** Prolongation of phospholipid-dependent coagulation tests **anti cardiolipin:** Immunoglobulins directed against phospholipids and b2 glycoprotein-1 **Anti-β2 glycoprotein-1 antibody** \*\*lupus anticoagulant: can't be done if patient is on anticoagulant medication note: Some **aspects of coagulation pathway are phospholipid dependent**. If there is **auto antibodies against this then there is prolongation of phospholipid dependent coagulation tests**

Answer 65

Th2 and Th17 cells * Inflammation with **Th2 and Th17 cells** predominating

Answer 66

Type I collagen α2 chains fibrillin 1 TGF-β

Answer 67

**Cytokines \>\>\> activation of fibroblasts \>\>\>** **development of fibrosis** ## Footnote **Cytokines \>\>\>** **activation of endothelial cells \>\>\>** **microvascular disease** **Loss of B cell tolerance to nuclear antigens**

Answer 68

* limited skin involvement: **does not progress beyond forearms** (and maybe perioral area) * **_CREST features_** Calcionisis Raynauds Erythroderma Sclerodactyly- tightening of the skin Telangictasia * **Also E**sophageal dysmotility + primary pulmonary hypertension

Answer 69

* **skin involvement beyond forearms** * CREST features: * calcinosis * raynauds phenomenon * erythoderma * Sclerodactyly * **T**elangiectasia * EXTENSIVE gastrointestinal involvement * interstitial pulmonary disease * kidney disease/renal crisis \>\> vascular renal problem- involves endothelial cells proliferating leading to a s**mall lumen and poor blood supply** \>\>\> severe hypertension)

Answer 70

anti-centromere

Answer 71

Anti-topoisomerase antibodies **(anti-Scl-70)** are good for diagnosing Anti-RNA polymerase Anti-Fibrillarin

Answer 72

**ANA staining**

Answer 73

* muscles * skeletal muscle- fatigue * lung - dyspnoea * heart - arrythmia * oesophagus - dysmotility * spares ocular muscles - unlike myasthenia gravis * **skin involvement** * heliotrope skin rash * gottron papules o **Immune complex mediated vasculiti**s (type III response)

Answer 74

* High serum creatine kinase/ CK * high aldolase, myoglobin, LDH, AST, ALT

Answer 75

Type III- immune complex mediated \*in the skin

Answer 76

Type IV- CD8 T cell mediated ## Footnote o Not much skin involvement - unlike Dermatomyositis o CD8 T cells kill myofibres via perforin/granzyme - type IV response

Answer 77

anti Jo 1 o Dermatomyositis \> Polymyositis: Anti-Mi2 (nuclear) o Anti-aminoacyl transfer RNA synthetase antibody (e.g. anti-Jo-1) (cytoplasmic)\*

Answer 78

Anti-signal recognition peptide antibody (nuclear and cytoplasmic)

Answer 79

* proixmal muscle weakness - **no skin involvement**

Answer 80

1. dermatomyositis * speckled ANA pattern * can see immune complex deposition 2. polymyositis * can see CD8+ T cells surrounding HLA class I myofibres

Answer 81

Small vessel vasculitis

Answer 82

* rare medium vessel vasculitis * usually associated with Hep B * Type III hypersensitivity reaction - immune complexes * anuerysm formation * Rosary bead appearance on histopathology

Answer 83

* Microscopic polyangiitis/ microscopic polyarteritis/ MPA * Granulomatosis with polyangitis/ Wegner's Granulomatosis * Churg-Strauss syndrome/ eosinophilic granulomatosis with polyangiitis/ eGPs

Answer 84

* Saddle nose * recurrent nosebleeds * haemoptysis * breathless * rapidly progressive glomerulonephritis → rapid decline in kidney function * constitutional symptoms * peripheral neuropathy

Answer 85

c-ANCA: **C**ytoplasmic fluorescence antibodies to the enzyme proteinase 3 * **\> 90% of patients with granulomatous polyangiitis with renal involvement**

Answer 86

**C**ytoplasmic fluorescence (c-ANCA- c for cytoplasm)

Answer 87

enzyme proteinase 3

Answer 88

accumulation of macrophages in bowman's capsule

Answer 89

* severe allergies * sinus problems * → progress to severe asthma prior to systemic vasculitis * **Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss syndrome)** * Asthma * Vasculitis * Eosinophilia * Treated with corticosteroids * Other conditions associated: * UC * PSC \*\*eosinophilic granulomatosis with polyangiitis

Answer 90

perinuclear (p-anca; p for perinuclear)

Answer 91

myeloperoxidase

Answer 92

anti-neutrophil cytoplasmic antibody Antibodies specific for antigens located in primary granules within the cytoplasm of neutrophils * Inflammation may lead to **expression of these antigens on the cell surface of neutrophils \>\>\> inflammatory response** **Anti-neutrophil cytoplasmic antibodies help in diagnosis and monitoring of disease activity**

Answer 93

Type 2 * Antibody engagement with cell surface antigens may lead to neutrophil activation (Type II hypersensitivity) * Activated neutrophils **interact with endothelial cells causing damage to vessels- vasculitis** **\*\*except polycarteritis nodosa which is type 3 hypersenstiivty\*\***

Answer 94

* microscopic polyangiitis (MPA) * eosinophilic granulomatous polyangiitis (eGPA)/ churg strauss syndrome * UC/ Primary Sclerosing Cholangitis

Answer 95

c-anca is more sensitive and specific

Answer 96

connective tissue disorders: * SLE * Sjrojens * diffuse and limited systemic sclerosis * myositis

Answer 97

small vessel vasculitides

Answer 98

Anti GLP-2b, 2a

Answer 99

Anti-Desmoglein 1 autoantigen - epidermal cadherin

Answer 100

IL1 and TNF

Answer 101

NOD2 (CARD-15) card-15, caspase activating recruitment domain-15

Answer 102

autoimmune diseases \*not in mixed pattern diseases either\*

Answer 103

more common in autoimmune disease \*can also get them in mixed pattern diseases\*

Answer 104

Mutation in TF AIRE

Answer 105

* **Adaptive immune response- T and B cells** **** * **Aberrant T and B cell responses** in **primary** (cell development) and **secondary** **lymphoid** (where cells respond) organs which lead to the **breaking of tolerance** with development of **immune reactivity towards self-antigens**

Answer 106

* However, for the mixed innate and adaptive response, it is just polygenic.

Answer 107

* **Germ line mutations- a**ffect DNA, and are in germ line cells * **Somatic mutation-** do not affect germ cells, not inherited, occurs after birth and present later in life

Answer 108

* **Genetics**- mutations affecting protein sequence * **Epigenetics**- (heritable) **change in gene expression** (e.g. via DNA methylation). May have the same sequence but different expression * Just because you have/do not have mutation does not mean you express it. * **MicroRNA (miRNA) is small, non-coding, single stranded RNA:** These bind to target mRNA and stop it from being able to produce protein.

Answer 109

polygenic diseases are common whereas monogenic diseases are rare

Answer 110

**ALPS= B** **Familial Mediterranean Fever= A** **IPEX= C**

Answer 111

IBD1 gene on chromosome 16, also known as NOD2 (card-15, caspase activating recruitment domain-15) 3 different mutations on this gene- associated with Crohns Note: . they are NOT necessary for development of crohn’s but are there in those with Crohns * NOD2 is expressed in the **cytoplasm of myeloid cells**- **macrophages, neutrophils and dendritic cells** * NOD2 acts as a microbial sensor + stimulates NFκB * **Activation of NOD2 induces autophagy (orderly degradation of cellular components) in dendritic cells**. In Crohns: there is **d*****isordered degradation which leads to inflammation:***expression of inflammation proteins + release of proteases + free radicals \>\>**granulomata formation and tissue damage**

Answer 112

Overactive innate immune response so need to suppress the inflammatory response * 1^st LINE- Corticosteroids * Azathioprine * **Anti-TNF****a antibodies** * Anti-IL12/23 antibodies

Answer 113

A- autoimmune B- Mixed pattern diseas e C- autoinflammatory

Answer 114

**There are _THREE_ forms of peripheral tolerance:** * T cells requiring co-stimulation for activation * Regulatory T cells * Immune privileged sites

Answer 115

* antibodies bind to cell-associated antigens, * this will **expose the binding site for C1q for complement** * this will lead to to _antibody-dependent destruction:_ * Antibodies can **activate COMPLEMENT (by binding to C1q**) * Antibodies can also **bind to Fc receptors on NK cells or to receptors on macrophages which will become activated and lead to inflammation \>\>\>\> cell death** * Binding of antibodies could also **interfere with receptors \>\>** receptor activation OR blockade Binding of antibody to receptor protein- sometimes referred as type 5 but usually just part of type 2 = can lead to activation and stimulation

Answer 116

* **Antibody binds to soluble antigens forming immune complexes** * The immune complexes deposit in the **blood vessels** (especially the **kidneys, joints and skin** \>\>\>\>\> * skin \>\>\> tiny bleeds in the skin, which gives rise to the purpuric rash * joints \>\>\> arthritis * kidneys \>\>\>\> glomerulonephritis: haematuria, proteinuria and renal failure

Answer 117

SLE SLE, antibodies against double stranded DNA, deposit particularly in the kidneys

Answer 118

- anti basement membrane antibodies against Type 4 collage on basement membrane - anti acyetylcholine **_receptor_** antibodies: blocks depolarisation signls = fluctuating muscle weakness - Anti Tsh receptor antibodies- IgG antibodies against TSH receptor = hyperstimulation = overproudciotn of thyroxine Anti gastric parietal cells antibodies + anti intrinsic factor antibodies \>\> causes vitamin B12 deficiency \>\> subacute combined degeneration anti islet cell antibodies, anti GAD antibodies, **anti IA2** \>\> not diagnostic for diagnosis anti thyroid peroxidase antiboides + antithyrglobulin antibodies \>\> hypothyroidism Anti cyclic citrulinated peptide antibodies- diagnostic + Rheumatoid factor- outdated

Answer 119

exception with transplantation so have foreign cell- antibody is against foreign cell not self cell

Answer 120

A- type 2 B- type 1 C- type 3 D- type 4

Answer 121

good pastures syndrome ## Footnote **High TLCO- gas transferring factor- indicates bleeding**

Answer 122

* **It is NOT specific** * So need to look at the specific antigen- **either proteinase 3 for cANCA or myeloperoxidase for pANCA**

Answer 123

Wegeners: more upper respiratory tract symptoms eg osebleeds and haemotysis GBM disease: PULMONARY HAEMORRHAGE - not in wegner's \*both can cause haematuria\*