Tolerance, Autoimmunity, Immunodeficiences. Tolerance is broadly defined as a state of unresponsiveness to an antigen, be it self or foreign Antigen-specific.

Tolerance, Autoimmunity,Immunodeficiences

Tolerance is broadly defined as a state of unresponsiveness to an antigen, be it self or foreign

Antigen-specific cell receives signals that eitheractivate OR inactivate the cell

Central tolerance to self antigens is acquired during development through the elimination or silencing of lymphocytes capable of binding self antigens

Peripheral tolerance is induced in mature lymphocytesin the periphery

Tolerance

Mechanisms to induce tolerance

Elimination of self-reactive lymphocytes = clonal deletion

(negative selective of T and B cells during development)

Silencing of self-reactive lymphocytes = clonal anergy

Clonal deletion of self-reactive lymphocytes occurs within primary lymphoid organs

Vh-DJh Vl-Jl

stem cell pro B pre B

D-Jh

IgM

immature B

IgD

IgM

mature B

Exit bone marrow

Cortex

Medulla

90% ofthymocytes diein cortex

10% ofthymocytes mature to T-cells

B-cells – bone marrow T-cells - thymus

Clonal deletion can also occur in the periphery

Mechanisms• Fas – FasL interactions: apoptosis• T suppressor/regulatory cells – Treg, CD4+CD25+

may kill by perforin/granzyme mechanism

Athymic nude

CD4+CD25- T cells Autoimmune diseases

Athymic nude

CD4+CD25- T cells+ CD4+CD25+ Treg

No disease

Clonal anergy of self-reactive lymphocytes can also occur in the periphery

CD28

Tissue cell has no B7

No co-stimulation

Anergy Inactivation of the cell –

nonresponder

T cells

B cells – can also be anergized in the absence of co-stimulation, usually CD40-CD40L

Other factors involved in Tolerance

-Dose/Route of Antigen

-Inappropriate cytokine responses

-anti-idiotypic responses

-Psychogenic factors

(poorly defined but could include the immunosuppressive effect of steroid hormones)

Tolerance to a fetus

The fetus is really an allograft with nonself MHC proteins & RBCs of the father so why is it not rejected by the mother?We know mothers’ makes antibodies against fathers’ MHC & RBCPotential mechanisms

Placenta – outer layer does not express classical MHC proteins expresses a molecule that inhibits NK cell killing

depletion of tryptophan – necessary T cell nutrientT cell tolerance to paternal ags, suppressed T cell responsesSecretion of cytokines that suppress TH1 cells – IL4, IL10, TGFRole for Treg cells?

“Immune privileged” sites

EyeTestisBrainOvary Placenta

Potential reasonsThe presence of FasL expressing cells that kill

infiltrating inflammatory T cells (Fas)Immunosuppressive cytokines

AutoimmunityAutoimmunity constitutes immune response against self

antigen. Autoimmunity may be benign or may be damaging to host

An immune response against self antigen(s) that results in the destruction of host tissue or damage to the function of an organ or tissue constitutes autoimmune disease

Autoimmunity can be thought of as a breakdown of tolerance, which is multi-layered, consisting of both central and peripheral mechanisms

Occasionally, self-reactive cells escape, resulting in autoimmune diseases (approximately 5% U.S. population)

Autoimmune diseases are multifactorial – genetic & environment

• Genetics. Presentation of self-antigens by MHC molecules: Linkage to certain MHC alleles in many autoimmune diseases

•Autoreactive lymphocytes

•Initiating Event: Environmental: Chemical exposureInfection: Viral and bacterial infection

molecular mimicry-cross reactivity between a microbial antigen with a self-antigen

•Gender: Females more frequently affected

•‘Handedness’: a tenuous but statistically-significant higher frequency in left-handed people

Contributing factors

Bacterial infections can lead to immune-mediated pathology

Classification of autoimmune disease

Historically – organ or systemic

Effector mechanism – antibody, complement, T cells

Antibody mediated diseases

Autoimmune hemolytic anemia – destruction of RBCs

Myasthenia Gravis – autoab to acetylcholine receptor, inhibits nerve impulse transmission (blocking ab)

Graves disease – autoab to receptor for thyroid-stimulating hormone, activates cell to release thyroid hormone (activating ab)

Systemic Lupus Erythematosus - wide spectrum of autoreactive antibodies, anti-nuclear antibodies against DNA,RNA, or nucleoproteins

Systemic Lupus Erythematosus

Characteristic butterfly rashDamage to several organsKidney – immune complex deposition can lead to activation of C, inflammation

Kidney damage causes the most mortality in SLE

Trigger unknown

T cell mediated diseases

Multiple Sclerosis – demyelinization of CNS tissueT cell response to myelin

Type 1 Insulin-Dependent Diabetes Mellitus – Cytotoxic T cells to pancreatic -islet cells

Hashimoto’s Thyroiditis - anti-thyroglobulin T/B-cells

Rheumatoid Arthritis – chronically inflamed synoviumactivated T cells, macrophages, B cellsinflammatory cytokines – TNF-, IL-1

Murine model of MS

Rheumatoid Arthritis

Immunotherapy with anti-TNF antibodies

Anti-IL-1R antagonist – to block action of IL-1

Immunodeficiencies

• Inherited immunodeficiences (genetic) are the most commonIgA deficiency the most common of these (1 in 800)The rest are rare (1 in 10,000)

• Acquired immunodeficiency- caused by malnutrition, seen in infants and children- caused by drugs or irradiation- caused by viral infection, seen in patients of all ages- alcoholism• age – very young or very old are “immunodeficient”

Immunodeficiencies – when one or more component of

the immune system is defective

Genetic defects may affect components of

innate immune system – phagocytic cells, complement

adaptive immune system – T cells, B cells

defects that affect CD4 T cells or the developmental stages of T and B cells severely compromise immune function. These are referred to as Severe Combined Immunodeficiency Disease (SCID)

both innate and adaptive immune systems

multiple defects that affect both arms of the immune system also result in severe compromise of immune functions. These are rare.

Immunodeficiency Is often recognized by recurrent infectionsThe type of infection depends on which component of the

immune system is compromised

Deficiency Disease___________________B cell Recurrent bacterial infectionsT cell Susceptibility to viruses, fungi, protozoansT & B cell Infections with bacteria, viruses, fungi,

protozoansPhagocytic cells Systemic infections with bacteria that

are of low virulenceComplement Bacterial infections

Defects in the innate arm of the immune system

Defective Genes/Proteins

Cells Affected

Decreased resistance to

Leukocyte Adhesion Molecules

Enzymes involved in intracellular killing

Complement Not Applicable

Phagocytes

PhagocytesPyogenic (pus forming)bacteria

Intracellular & Extracellularmicrobes

Pyogenic (pus forming)bacteria and Neisseria

Defective genes/proteins

Cell type affected

phenotype Susceptibility to

Bruton’s tyrosine kinase

(x-linked)

B cells Agammaglobu-linemia

Extracellular bacteria

CD40 ligand (x-linked)

T cells No antibody responses, no

isotype switching

Extracellular bacteria

IgA deficiency, CVID (IgG and

IgA def)

B cells No IgA or IgG antibodies

Respiratory infections

Expression of MHC class I

Nucleated cells

No CD8 T cells viral infections

Expression of MHC class II

APC No CD4 T cells,

SCID

generalized

Defects in the adaptive arm of the immune system

Generalized defects of the adaptive immune system

Defective gene/protein

Cell type affected

phenotype susceptibility

DiGeorge Syndrome (Athymic)

T-cells SCID general

Purine degradation

enzymes

Developing

T cells SCID general

Recombinases, DNA repair enzymes

Developing

B and T cells SCID general

chain of cytokine receptors (x-linked)

T and B cells SCID general

Note: chain is shared by receptors for IL2, IL4, IL7, IL9 and IL15

Acquired Immunodeficiencies

Severe immunodeficiency caused by HIV (AIDS) generalized immunosuppression due to loss of CD4 T cells.

Immune suppression induced by Epstein-Barr Virus (EBV) following infectious mononucleosis.

Radiation or Cytotoxic drugs

Malnutrition

Alcoholism

•Innate Immunity: ELISA for complement components,Cytotoxicity/Phagocytosis assays

•Humoral Immunity: ELISA for antibody (total and specific)

enumerate B-cellsproliferative capacity

•Cellular Immunity: Th- skin testing (DTH or Mantoux test),

proliferation, cytokine production by ELISA,

enumerate CD4+ T-cells

Tc- Cytotoxicity testing, IFN-production,

enumerate CD8+ T-cells

Measuring Immune Responses to determine immunodeficiency