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Tolerance, Autoimmunity,
Immunodeficiences
Tolerance
Tolerance is broadly defined as a state of unresponsiveness
to an antigen, be it self or foreign
Antigen-specific cell receives signals that either
activate 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 lymphocytes
in the periphery
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
stem cell
pro B
D-Jh
Vh-DJh
pre B
immature B
Vl-Jl
IgM
Cortex
90% of
thymocytes die
in cortex
Medulla
IgM
Exit bone
marrow
mature B
10% of
thymocytes
mature to T-cells
IgD
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
Autoimmune diseases
CD4+CD25- T cells
Athymic nude
No disease
CD4+CD25- T cells
+ CD4+CD25+ Treg
Athymic nude
Clonal anergy of self-reactive lymphocytes
can also occur in the periphery
T cells
Tissue cell has no B7
No co-stimulation
CD28
Anergy
Inactivation of the cell –
nonresponder
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 & RBC
Potential mechanisms
Placenta – outer layer does not express classical MHC proteins
expresses a molecule that inhibits NK cell killing
depletion of tryptophan – necessary T cell nutrient
T cell tolerance to paternal ags, suppressed T cell responses
Secretion of cytokines that suppress TH1 cells – IL4, IL10, TGFb
Role for Treg cells?
“Immune privileged” sites
Eye
Testis
Brain
Ovary
Placenta
Potential reasons
The presence of FasL expressing cells that kill
infiltrating inflammatory T cells (Fas)
Immunosuppressive cytokines
Autoimmunity
Autoimmunity 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
Contributing factors
• Genetics. Presentation of self-antigens by MHC molecules:
Linkage to certain MHC alleles in many autoimmune diseases
•Initiating Event:
Environmental: Chemical exposure
Infection: Viral and bacterial infection
molecular mimicry-cross reactivity between a
microbial antigen with a self-antigen
•Autoreactive lymphocytes
•Gender: Females more frequently affected
•‘Handedness’: a tenuous but statistically-significant
higher frequency in left-handed people
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 thyroidstimulating 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 rash
Damage to several organs
Kidney – 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 tissue
T cell response to myelin
Type 1 Insulin-Dependent Diabetes Mellitus –
Cytotoxic T cells to pancreatic b-islet cells
Hashimoto’s Thyroiditis - anti-thyroglobulin T/B-cells
Rheumatoid Arthritis – chronically inflamed synovium
activated T cells, macrophages, B cells
inflammatory cytokines – TNF-a, IL-1
Murine model of MS
Rheumatoid Arthritis
Immunotherapy with anti-TNF a antibodies
Anti-IL-1bR antagonist – to block action of IL-1b
Immunodeficiencies
Immunodeficiencies – when one or more component of
the immune system is defective
• Inherited immunodeficiences (genetic) are the most common
IgA 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”
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 infections
The type of infection depends on which component of the
immune system is compromised
Deficiency
B cell
T cell
T & B cell
Phagocytic cells
Complement
Disease___________________
Recurrent bacterial infections
Susceptibility to viruses, fungi, protozoans
Infections with bacteria, viruses, fungi,
protozoans
Systemic infections with bacteria that
are of low virulence
Bacterial infections
Defects in the innate arm of the immune system
Defective
Genes/Proteins
Leukocyte Adhesion
Molecules
Enzymes involved in
intracellular killing
Complement
Cells Affected
Decreased resistance to
Phagocytes
Pyogenic (pus forming)
bacteria
Phagocytes
Intracellular & Extracellular
microbes
Not Applicable
Pyogenic (pus forming)
bacteria and Neisseria
Defects in the adaptive arm of the immune system
Defective
genes/proteins
Cell type
affected
phenotype
Susceptibility to
Bruton’s tyrosine
kinase
B cells
Agammaglobulinemia
Extracellular
bacteria
CD40 ligand
T cells
No antibody
responses, no
isotype switching
Extracellular
bacteria
B cells
No IgA or IgG
antibodies
Respiratory
infections
Nucleated
cells
No CD8 T cells
viral infections
APC
No CD4 T cells,
generalized
(x-linked)
(x-linked)
IgA deficiency,
CVID (IgG and
IgA def)
Expression of
MHC class I
Expression of
MHC class II
SCID
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
SCID
general
Recombinases,
DNA repair
enzymes
Developing
SCID
general
SCID
general
 chain of
cytokine
receptors
T cells
B and T cells
T and B cells
(x-linked)
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
Measuring Immune Responses to determine immunodeficiency
•Innate Immunity: ELISA for complement components,
Cytotoxicity/Phagocytosis assays
•Humoral Immunity: ELISA for antibody (total and specific)
enumerate B-cells
proliferative 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