Manipulation of the immune response · 2019-02-28 · 21 Treatment of unwanted immune response Prescription for MS and Crohn’s disease Endothelium cells express VCAM-1 Effector

Manipulation of the immune response

➢ Autoimmune diseases and the pathogenic mechanism

➢ Treatment of unwanted immune responses

Ida Berg – Molecular Immunology – 27.06.2018

Illustration by Julia Yellow via https://www.spectrumnews.org © 2018 Simons Foundation

Ida Berg – Manipulation of the immune response – 26.06.20182

Content

Autoimmune diseases

▪ Self-Tolerance mechanisms

▪ Immune response

▪ Classification

▪ Pathogenic mechanisms of

▪ Systemic Lupus Erythematosus (SLE)

▪ Multiple Sclerosis (MS)

Treatment of unwanted immune response

▪ Conventional drugs

▪ New biologic agents

3

Self-Tolerance Mechanisms

Variety of mechanisms at

different sites and stages of

development

▪ Low level of autoreactivity

is physiologic and crucial to

normal immune function


Janeway’s Immunobiology, 2017

4

Central tolerance

▪ Negative selection of

thymocytes in the cortex

or medulla


Self-Tolerance

Mechanisms

TCR: T cell receptor

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Self-Tolerance Mechanisms

Elimination of autoreactive B cells in germinal

centers

▪ Hypermutated self-reactive B cell encounters

strong cross-linking of its B-cell receptor

➢ Apoptosis


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Development of autoimmune disease


Requirements

▪ Triggers often not clear

▪ Ca. 5 % of the population of western countries

are affected

▪ Starts often during adulthood

▪ Many different symptoms that result in tissue

damage

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Classification

Systemic autoimmune diseases

▪ Many tissues are affected

▪ Effector cells target ubiquitous/ abundant autoantigens

▪ Chronical

Organ specific autoimmune diseases

▪ Effector cells target autoantigens restricted to particular

organs

▪ Immune destruction of the target tissue can end

autoimmunity activity

CNS: Central nervous system

8

Classification

→ Occurrence often in clusters

Autoimmune Diseases

Organ Specific


▪ Crohn’s disease

▪ Psoriasis

▪ Type I diabetes mellitus

▪ Vitiligo

▪ Graves’ disease

Systemic

▪ Systemic lupus erythematosus

(SLE)

▪ Rheumatoid arthritis

▪ Scleroderma

▪ Polymyositis



All aspects of the immune response are involved

Autoantibodies

▪ Anti-receptor AB cause disease by stimulating or blocking receptor function

▪ As immune complexes: complement activation and ligation of Fc receptor cause

inflammation

▪ Antibody-mediated AD can be transferred across placenta to fetus/infant

T cells

▪ Recognize self peptides of self MHC

▪ Local inflammation or direct tissue damage

▪ Help B cells with production of antibodies

B cells

▪ Presenting antigens to stimulate T cells

▪ Secreting pathogenic antibodies

AB: antibody; AD: autoimmune disease


Autoantibody-mediated inflammation

Postive feedback loop from inflammation

▪ Early activation phase: few autoantigens

▪ Chronic inflammation leads to tissue damage

▪ Sequestration: exposure of normally “hidden” antigens

▪ Additional autoreactive B cells are recruited

▪ Epitope spreading leads to the targeting of additional antigens

➢ Perpetuation and amplification of disease

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Autoantibody-mediated inflammation



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Classification

→ Occurrence often in clusters

Autoimmune Diseases

Organ Specific


▪ Crohn’s disease

▪ Psoriasis

▪ Type I diabetes mellitus

▪ Vitiligo

▪ Graves’ disease

Systemic

▪ Systemic lupus erythematosus

(SLE)

▪ Rheumatoid arthritis

▪ Scleroderma

▪ Polymyositis


13

Systemic Lupus Erythematosus (SLE)

A T-cell-mediated disease

▪ Target: intracellular nucleoprotein antigens (chromatin, spliceosome complex)

Pathophysiology

▪ Systemic inflammation affecting multiple organs (skin, kidney, joints)

▪ Deposition of immune complexes in walls of small blood vessels

• Deposition in renal glomerulus (see below) causes renal failure


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SLE

A T-cell-mediated disease

▪ Target: intracellular

nucleoprotein antigens

(chromatin, spliceosome

complex)

Chronic antibody production

▪ Overproduction of

antibody:nucleic acid immune

complexes

▪ Defective clearance of

immune complex

▪ Activation of low-affinity self-

reactive lymphpocytes



15

Multiple Sclerosis

T-cell-mediated neurologic disease

▪ Target: CNS myelin antigens

▪ Two main phases

• Relapse: symptoms

• Remission: full or partial recovery

• Later progressive phase

Pathophysiology

▪ Lesions in white matter (scars)

▪ Demyelination

▪ Inflammation

▪ Blood-brain barrier disruption

▪ Paralysis


16

Multiple Sclerosis

T-cell-mediated neurologic disease

▪ Target: Myelin basic protein, proteolipid protein and myelin oligodendrocyte

glycoprotein

▪ Brain and spinal cord invasion by CD4 T-cells, muscle weakness

Mechanism after blood-brain barrier disruption

▪ Migration of CD4 T-cells out of blood vessels into brain tissue

(Integrin-VCAM interaction)

▪ T cells reencounter their specific antigen presented by MHC II on microglia

▪ Inflammation causes infiltration by TH17 and TH1 effector CD4 T cells and

release of IL-17, INF-γ


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Multiple Sclerosis

Pathogenic mechanism

▪ Different Autoimmune diseases



18


Conventional drugs


Anti-

inflammatory

Target

▪ Gen

transcription

Cytotoxic

Target

▪ Dividing cells

Immuno-

suppressive

Target

▪ Specific

signaling

pathways

19


Corticosteroid therapy

▪ Class of Steroid hormones

▪ Corticosteroids have potent broad spectrum of

actions

▪ Also many side-effects

▪ Should be combined with other drugs (cytotoxic

and immunosuppressive)



20


New biologic agents


Inhibit

lymphocyte

traffic

Target

▪ Integrins

▪ B cells

Block specific

cellular

interaction

Target

▪ T cells

Affect terminal

effector

mechanisms

Target

▪ Cytokines

Monoclonal antibodies Immunomodulatory proteins

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Prescription for MS and Crohn’s disease

▪ Endothelium cells express VCAM-1

▪ Effector lymphocytes express α4:β1 integrin

▪ Monoclonal antibody Natalizumab is specific

for α4 subunit

➢ Lymphocytes cannot enter the tissue


MS: multiple sclerosis; VCAM: vascular cell adhesion molecules

22

SUMMARY

Autoimmune diseases

▪ Classification: Systemic, Organ-specific

▪ All aspects of the immune response are involved and operate often in parallel

• T cells, B cells, antibodies


▪ Corticosteroids are anti-inflammatory drugs and normally combined with

cytotoxic or immunosuppressive drugs

▪ Immunomodulatory agents (monoclonal antibodies or fusion proteins) inhibit

the inflammatory actions of TNF-α


23

References

▪ Murphy, K., Travers, P., Walport, M., Janeway, C. (2017): Janeway’s

Immunobiology (9th ed.). New York: Garland Science. Pages: 333, 643-669

▪ Steinman, L. (2012): The discovery of natalizumab, a potent therapeutic for

multiple sclerosis. J .Cell Biol. Vol. 199 No.3, 413-416


Thank you for your attention!

Any questions?

Illustration by Julia Yellow via https://www.spectrumnews.org © 2018 Simons Foundation

Documents

Manipulation of the immune response · 2019-02-28 · 21 Treatment of unwanted immune response Prescription for MS and Crohn’s disease Endothelium cells express VCAM-1 Effector