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Immunology: Research + Clinic > HC7: Autoimmune disease and therapeutic antibodies > Flashcards

HC7: Autoimmune disease and therapeutic antibodies Flashcards

HC 7

1
Q

Autoimmune disease types

A
  • Organ specific or systemic
    > the disease is always throughout whole body, but could focus on organs
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2
Q

Autoimmune disease age

A

Mostly young age

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3
Q

Common features autoimmune diseases

A
  • Central and peripheral tolerance
  • Genetic predisposition and environmental factors like HLA type for strength of immune response
  • Autoantibodies, auto-reactive B/T-cells
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4
Q

Acute rheumatism

A
  • Streptococcal infection: cell wall stimulates antibody response
  • With some earlier species: some antibodies cross-react with heart valve, causing rheumatic fever
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5
Q

Rheumatioid arthritis (RA) symptoms

A
  • Common form rheuma
  • Young patients mostly, in 20s, mostly women
  • Pain and swelled hands
  • Inflammation in joints > cartilage (kraakbeen) of joints is destroyed
  • Knobs on hands
  • attacks in phases
  • synoviocytes inflammation
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6
Q

Synoviocyte inflammation: synovitis

A

Mucosa of the joint > grows > inflammation > blood vessels enter tissue > inflammatory cells enter to destroy cartilage and bone
» in RA
> damage caused causes more inflammation: vicious cycle

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7
Q

Cytokines involved in chronic inflammatory arthritis (RA)

A
  • TNFa, IL-6, IFN-y, IL-1, OPGL, IL-17
    > immune cells induced
    > influence osteoblasts and osteoclasts
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8
Q

Chronic inflammation in joint leads to bone destruction evident as erosions. What happens when prolonged severe chronic arthritis?

A

Deformity and disability

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9
Q

Rheumatoid factors (RFs)

A

Agglutanation of RBCs by antibody against serum gamma-globulins (y-globulins) against IgG > IgM against self-antigen IgG Fc (auto-antibodies)
> these are called RFs

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10
Q

RA: citrullination of proteins

A
  • Antibodies bind citrullinated proteins
  • Citrullination: breakdown process of cell, proteins are broken down, and in this process the PAD enzyme converts arginine in citrulline > citrullination (make protein more susceptible for proteolytic degradation).
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11
Q

Presence RA Abs

A

Present before expression of arthritis
> anti-CCP (anti citrullinated proteins) and IgM-RF

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12
Q

Trigger for RA

A

Can be smoking
> inflammation (chronic bronchitis)
> when right gene composition (specific HLA type (HLA-DR2) 2 gene: anti-CCP antibodies made
> RFs that bind immune complex of low affinity anti-CCP IgG made
> Take five IgGs at one time, RF is IgM, pentamer with high avidity
> activation complement
> damage induced
> more inflammation
> vicious cycle of damage and inflammation

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13
Q

Phases RA

A
  • Pre-articular or lymphoid phase: autoimmunity: anti-CCP and RFs
  • Transition phase
  • Articular phase
    > articular localization: osteoporosis, functional decline, cardiovascular disease
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14
Q

Ankylosing spondylarthritis and HLA

A

Most known HLA associated disease: HLA-B27
> 10% HLA-B27 prevalence
> pain in back
> 10% chance of diagnosing someone wrong when HLA typing.
> 87% relative risk
> known as Bechterew disease

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15
Q

Becheterew disease and symptoms

A
  • Young men affected
  • Spinal joints
    > stiffen in back and SI joints affected (sacroiliac joints in hip)
  • inflammation in other joints as well
  • chronic inflammation > anemia > higher risk cardiovascular disease and fatigue
  • Create Bamboo Spine: vertebrae grow together
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16
Q

Is HLA-type enough for Bechterew diagnosis

A

No more needed: 2 other SpA (ankylosing spondylarthritis)
> like family background
> uveitis: inflammation in eye: less common in HLA-B27

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17
Q

What happens to HLA-B27 in Bechterew?

A

Wrong folding? Interaction with KIR (T-cells and NK-cells are KIR+)? Modulation microbiome and indirect modulation acquired immunity? Unknown yet.

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18
Q

Jicht disease

A
  • Men mostly
  • Alcohol consumption, renal problems
  • Red feet, very painful acute attacks
    (Bechterew and RA are more chronic: morning stiffness)
  • joints are destroyed
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19
Q

Jicht trophi

A

Large knobs with white paste inside
> uric acid crystals inside them: metabolic disease
> urate oxidase absent in humans: not metabolized
> neutrophils take the crystals up but die: dead neutrophils are white paste
> concentration uric acid to high > precipatation (neerslag) of uric acid crystals)
» derived from nucleic acids from nutrients and purine metabolism

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20
Q

Jicht causes

A
  • Genetic predisposal for high uric acid > Jicht
  • Renal dysfunction > Jicht
  • Too much alcohol > Jicht
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21
Q

Bechterew kind of disease

A

T-cell mediated autoimmune disease

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22
Q

RA kind of disease

A

Antibody mediated autoimmune disease

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23
Q

Jicht kind of disease

A

Metabolic disease, causing inflammation of joints

24
Q

Multiple sclerosis (MS) character

A
  • Autoimmune disease of nervous system
  • Inflammation of retina is possible
  • Nervous paths destroyed in spinal cord and brain
  • In young women mostly, like RA
  • Autoreactive lymphocytes induce inflammatory reaction leading to demyelination and damage to axons
  • When attacks: damage, nervous deficit over time
25
2 types of MS
- Relapsing remitting RRMS (85%): peaks which pass threshold of being clinical and slow increase towards SPMS: secondary progressive MS. After reaching threshold in progressive trend, progressive increase in severity and constantly clinical - Primary progressive MS (PPMS) (15%): progressive MS towards clinical threshold with smaller and less prevalent attacks
26
Risk factors MS
- Genetic: HLA-DR2 - Women - Smoking - Maybe EBV (Epstein-Barr Virus)
27
Pathogenesis MS
Unknown trigger sets up inflammation in brain > at sites inflammation, activates T-cells auto-reactive for brain antigens cross blood-brain barrier and enter brain, where they re-encounter antigens on microglial cells and secrete cytokines like GM-CSF and IFN-y > increase inflammation and more immune cells and complement > chronic autoimmune disease through positive feedback from inflammation
28
Psoriasis
Class 1 (MHCI, CTLs) mediated disease > inflammation of skin, against skin associated antigens
29
Hashimoto thyroiditis
Autoantibodies and autoreactive T-cells against thyroid antigens > hypothyroidism > underproduction thyroid hormones
30
Systemic lupus erythematosus
Autoantibodies and autoreactive T-cells in kidneys, brain > autoreactivity against DNA and nucleosomes >> not organ specific >> young people affected >> can be very acute: systemic: spinal cord, kidneys etc, quick destruction
31
Vasculitis
Precipitation of autoreactive cells in circulation, happens in severe cases of for example Lupus
32
Therapy autoimmune disease
- Steroids - Cytotoxic drugs - Cyclosporine etc (T-cell inhibition) - JAK-inhibitors - Biologicals > mAbs
33
JAK-inhibitors
- Target JAK-STAT pathway > inhibit inflammation > for RA for example > coupled to cytokines which are pro-inflammatory or cytokine receptors
34
Biologicals: hybridoma technology
- Fuse spleen cell with myeloma cell > monoclonal antibodies made > one antibody secreting cell clone that can replicate indefinitively >> from one clone, for one antigen of interest >> from polyclonal to monoclonal Ab therapy > Select for monoclonal population
35
mAb treatment use in autoimmune disease
When selectively block something > selective depletion of autoreactive lymphocytes for autoimmune disease > biologicals that block TNFa, IL-1, IL-6 to alleviate autoimmune disease > to block cell migration to sites of inflammation for MS (block blood brain barrier crossing) > block co-stimulatory pathways to activate lymphocytes for RA
36
mAb types
-omab: fully mouse: autoreactivity against it -ximab: chimeric: change variable part of antibody: VH/VLs -zumab: humanized: just CDRs are mouse, anti-idiotypic antibodies possible -umab: fully human, not immunogenic
37
TNF-inhibitors
Monoclonal antibodies used mostly > Infliximab IFX: chimeric > Adalimumab ADL: human > Golimumab GLM: human, best binding affinity > Etanercept ETN: TNF receptor with Ab Fc tail > Certoluzimab CZP: small fragment of only Fab and no Fc tail
38
Infliximab and Adalimumab are most used anti-TNF mAbs, why
Golimumab with strongest binding is very expensive
39
Certoluzimab application
In pregnancy > in third trimester, FcRn brings IgG from mother to child > you do not want anti-TNF in child > no Fc tail, only Fab fragment > cannot be bound by FcRn: not transferred
40
Problem infliximab
Is chimeric > anti-antibodies, anti-IFX > if immune response stronger than the infliximab > only immune complexes made (anti-Abs on IFX) and no effect of treatments > immune complexes can create attacks when IV is on
41
Therapeutic antibodies for RA
- Anti-TNF - Anti-IL-6 - Anti-CD28: Abatacept (block co-stimulation T-cell) - Anti-CD20: Rituximab: for B-cell > when mAb treatment stopped: relapse
42
Screening when anti-TNF
when tuberculosis latent in lungs and anti-TNF given, tuberculosis in whole body and destroys everything: so screening is important
43
Rituximab
Anti-CD20 for example against RA > removes naive B-cells and memory B-cells in circulation > does not remove plasmablasts (PBs), plasma cells (PCs), long lived plasma cells and memory cells in tissue > repeated infusions required > Rituximab is cancer therapy for B-cell leukemia > induce apoptosis B-cells
44
Rituximab in RA combined with:
Methotrexate > Rituximab + methotrexate given when anto-TNF treatment not possible or not wanted by patient
45
Problem Rituximab and SARS-CoV-2
Vaccination did not work for Sars-CoV-2 > humoral immune response does not work (via B-cells), antibodies do not protect against Sars-CoV-2
46
MS treatment mAbs
- Natalizumab - Rituximab / Ocrelizumab (B-cell depletion)
47
Natalizumab
- Prevent lymphocytes from crossing blood-brain barrier - Severe demyelination disease caused by reactivation of Jacob-Creutzfeldt virus is risk: screening beforehand - Immunocompromised patients: progressive multifocal leukoencephalopathy
48
Rituximab / Ocrelizumab for MS
- When Natalizumab does not work - Ocrelizumab binds CD20 like Rituximab > B-cell depltion > Rituximab is chimeric and Ocrelizumab humanized > cells which kill Rituximab are also killed and Ocrelizumab is low immunogenic > gain control of disease
49
Does Rituximab work against Ankylosing Spondylitis / spondylarthritis / Bechterew?
No
50
Disadvantage Immune Checkpoint Inhibition in immune-oncology?
If too much response > autoimmunity > T-cells become overactive >> PD-1, PD-L1 and CTLA4 blocked >> inhibit immune checkpoint of tumor cell with anti-PD-L1 and anti-PD-1
51
CAR T-cells against B-cells
Chimeric antigen receptor CART-19 against CD19 > B-cells >> whereas anti-CD20 (Rituximab) works against naive B-cell and memory B-cell in circulation, CAR T-cells with CART19 receptor work against pro- B-cells and plasmablasts as well. > broader target
52
Rituximab for SLE (Lupus) (Systemic lupus erythematosus)
Low effect anti-CD20 > does not work against plasmablast >> however, CART19 cells against the B-cells work better >> with only one treatment, complete remission
53
CAR T-cell challenges
Toxic effects: get very sick Lymphodepletion T-cell immunity Fertility Permanent organ damage Costs
54
Bispecific T-cell engager (BiTE) therapy for refractory arthritis
Anti-CD3 (T-cell) and anti-CD19 (B-cell) bispecific > Blinatumomab
55
Why does Rituximab not work against SLE, and why do CAR T-cells work?
- Antibodies (Rituximab) are hydrophilic and stay in circulation > CAR T-cells can go to lymph nodes: deeper depletion > CAR T-cells work against pro-B cell and plasmablast > first chemo and then CAR T-cells to make space for it. > not chemo if Rituximab

Immunology: Research + Clinic (7 decks)

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