Immunity Overview (COMPLETE SET)

What is pathologic autoimmunity?

Presence of autoimmune reaction

Primary (not secondary to tissue)

Absence of other causes

What does it mean when autoimmunity is organ specific?

Ags only expressed in certain tissues

• Diabetes: Abs to B-cells of the pancreas

What does it mean when autoimmunity is systemic/generalized?

Ags expression is widespread

• Systemic Lupus Erythematosus (SLE)

What is immunologic tolerance?

State at which the individual is incapable of developing an immune response to a specific Ag

What is self tolerance?

Lack of immune responsiveness to self-antigens (Ags)

What is central tolerance?

Elimination of overreactive self-reactive lymphocytes (B-cells, T-cells)

• Negative selection in the thymus (AIRE gene)

Not 100% foul proof

What gene is important for thymic negative selection?

AIRE gene

What is peripheral tolerance?

Cells that make it past central tolerance

What mechanisms contribute to peripheral tolerance?

Anergy — Irreversible inactivation of lymphocytes

Treg suppression (CD4, CD25, FoxP3)

Clonal deletion

Antigen sequestration

What are immune-privileged sites?

Sites protected from immune surveillance such as:

• Eye

• Brain

• Testes

What are the major mechanisms of autoimmunity?

Failure of tolerance

Abnormal self-antigen display

Molecular mimicry

• Ex. Rheumatic heart disease

Genetic susceptibility

• HLA genes

• Familial clustering (increased in twins)

What can occur during a failure of tolerance?

Defective tolerance or regulation

Abnormal display of self-antigens

Initial innate immune response

How does abnormal display of self-antigens occur?

Structural changes due to stress or injury lead to epitopes previously not recognized

Which HLA genes are strongly associated with autoimmune disease?

HLA-DR and HLA-DQ (Class II)

Why is treating rheumatic heart disease a good example of molecular minimcry?

Medication/Antibodies used for strep ALSO target heart cells

What is SLE?

Systemic Lupus Erythematosus

What organs are commonly affected in SLE?

Skin — Malar rash

Kidney

Joints

Spleen — Onion skin lesions

Serosal membranes

Heart

CNS

What are important antibodies in SLE?

ANA

Anti-dsDNA

Anti-Smith

Antiphospholipid antibodies

Abs against:

• RBCs

• WBCs

• Platelets

Which antibodies are virtually diagnostic for SLE?

Anti-dsDNA and anti-Smith antibodies

What is the classic rash of SLE?

Malar (“butterfly”) rash

What is SOAP BRAIN MD for SLE?

Diagnostic criteria

• Serositis

• Oral ulcers

• Arthritis

• Photosensitivity

• Blood disorders

• Renal involvement

• ANA+

• Immunologic (Anti-Sm, anti-dsDNA)

• Neurologic Sx

• Malar rash

• Discoid rash

What are the patterns of immunofluorescence for SLE?

Homogenous or diffuse

Rim or peripheral

Speckled

Nucleolar

Why is immunofluorescence used for SLE?

Highly sensitive

Not highly specific

Patterns are not absolutely specific for type of antibody

Antibodies to ds-DNA and to Smith (Sm) antigen (non-DNA) are virtually diagnostic of SL

What is the most serious form of lupus nephritis?

Class IV: diffuse proliferative glomerulonephritis

What is the most common cause of death in SLE?

Renal failure

What type of joint disease occurs in SLE?

Nonerosive synovitis

What cardiac lesion is classic for SLE?

Libman-Sacks endocarditis

Which lupus nephritis results in end-stage renal disease?

Class VI: advanced sclerosing lupus nephritis

What is the clinical course in SLE?

Difficult to diagnosis in many cases

• Benign, indolent

• Malignant, rapid

• Remissions and relapses

• 90% 5 year survival

• 80% 10 year survival

Treatment — Steroids and immunosuppressive (mAb)

What are the hallmark symptoms of Sjögren syndrome?

Dry eyes (keratoconjunctivitis sicca)

Dry mouth (xerostomia)

T-cell immune mediated destruction of lacrimal and salivary glands

What is the primary/isolated form of Sjögren syndrome?

Sicca syndrome

What is the secondary form of Sjögren syndrome?

Associated with other autoimmune disorder in about 60% of patients

Which antibodies are associated with Sjögren syndrome?

Anti-SSA (Ro) and anti-SSB (La)

AutoAbs to:

• SS-A (Ro)

• SS-B (La)

• RNP Ags

90% of pts; not entirely specific

What genetics factors are associated with Sjögren syndrome?

Inheritance of certain MHC II molecules

Loss of tolerance of CD4+ T cells

What happens to the involved secretory glands of Sjögren syndrome?

Intense lymphocyte and plasma cell infiltrates with germinal center formation

Loss of normal architecture

Mucosal atrophy, fibrosis

Ulceration of conjunctiva, oral mucosa, and nasal septum

What malignancy risk is increased by 40 fold in Sjögren syndrome?

MALT lymphoma/non-Hodgkin B-cell lymphoma

What are the major features of systemic sclerosis?

Chronic autoimmune inflammation (T-cell mediated)

Small vessel damage

Progressive fibrosis

What are the 2 major categories of systemic sclerosis?

Diffuse scleroderma

Limited scleroderma

What is diffuse scleroderma?

Symmetric widespread skin fibrosis, with rapid progression and early visceral involvement

What is a symptom of limited scleroderma?

CREST syndrome

What does CREST stand for?

Calcinosis

Raynaud phenomenon

Esophageal dysmotility

Sclerodactyly

Telangiectasia

What are the overlap syndromes of systemic sclerosis?

Either diffuse or limited scleroderma with typical features of one or more other autoimmune diseases like MCTD

Which anti-nuclear protein antibody is associated with diffuse scleroderma?

Scl-70 (anti-topoisomerase I)

Which anti-nuclear protein antibody is associated with limited (CREST) scleroderma?

Centromere

What is often the first symptom of systemic sclerosis?

Raynaud phenomenon

What are the common symptoms of systemic sclerosis?

Raynaud’s phenomenon

Hands atrophy/immobile

Dysphagia

Malabsorption

Dyspnea and chronic cough

Pulmonary HTN with cor pulmonale

Renal failure → Malignant HTN

What are patient outcomes of systemic sclerosis?

Most progress slowly

Life span normal if NO renal involvement

10 year survival is 35-70%

What form of systemic sclerosis has the better prognosis?

CREST

What is inflammatory myopathies?

Rare disorder with immune-mediated muscle injury and inflammation

• Occurs alone OR with other disorders such as systemic sclerosis

What are the major inflammatory myopathies?

Polymyositis

Dermatomyositis

Inclusion body myositis

What disorders overlap in mixed connective tissue disease?

SLE — Most common

Systemic sclerosis

Polymyositis

What antibody is associated with mixed connective tissue disease?

Anti-U1 RNP

What does mixed connective tissue disease typically present with?

Synovitis of fingers

Raynaud’s

Mild myositis

What is an immunodeficiency disorder?

Increased susceptibility to infection due to failure of one or more components of the immune system

What is the difference between primary and secondary immunodeficiency?

Inherited

Acquired

What are some examples of primary/inherited immunodeficiency?

XLA (Bruton’s)

CVID

SCID

IgA deficiency

HIgM

DiGeorge

Wiskott-Aldridge

Ataxia Telangiectasia

What are some examples of secondary/acquired immunodeficiency?

Therapy-induced

Malnutrition

Infection

Cancer

Renal disease

Sarcoidosis

What causes XLA (X-linked Agammaglobulinemia)?

Mutation in BTK tyrosine kinase causing failed B-cell maturation

Normal T-cell-mediated response

What immunoglobulin levels are seen in XLA?

Very low/absent all immunoglobulins

When does XLA present?

Around 6 months when maternal IgG disappears

What infections are common in XLA?

Encapsulated bacteria:

• H. influenzae

• S. pneumoniae

• S. aureus

All susceptible to Giardia lamblia due to lack of IgA

How is XLA treated?

Transfusion of IV Ig from pooled serum

How does CVID differ from XLA?

B-cells are present but fail to mature into plasma cells

Sexes affected equally

Symptoms occur in the second or third decade of life

What complications are associated with CVID?

Autoimmunity and lymphoma

What does CVID stand for?

Common variable immunodeficiency

What is the most common primary immunodeficiency?

Isolated IgA deficiency

• Significant association with autoimmune diseases

Why do IgA-deficient patients get respiratory/GI infections?

IgA is the main mucosal antibody

What mechanisms causes isolated IgA deficiency?

A block in terminal differentiation of IgA-secreting B cells into plasma cells

• Normal levels of IgM and IgG

What causes Hyper-IgM syndrome?

CD40L mutation causing defective class switching

What immunoglobulin pattern occurs in Hyper-IgM syndrome?

High/normal IgM

Low:

• IgG

• IgA

• IgE

What is the normal Ig sequence?

IgM → IgG → IgA → IgE

• Isotype switching

Where is the CD40L gene located?

On the X chromosome

What is X-HIgM?

A defect in cell-mediated immunity

• Ex. Defect in CD40-CD40L interaction

  • Critical for the TH cell-mediated activation of macrophages in cell-mediated immunity

Why is X-SCID called “combined” immunodeficiency?

Both T-cells and B-cell immunity are impaired

• Failure of IL signaling

• Defective lymphopoiesis

What is X-linked SCID?

Most common

Mutation in cytokine receptor

• Directly reduces T-cell production

• Indirectly reduces B-cell production

  • No T-cell signal to secrete antibodies

What does SCID stand for?

Severe combined immunodeficiency (SCID)

What enzyme deficiency commonly causes autosomal recessive SCID?

Adenosine deaminase (ADA) deficiency

What does ADA deficiency directly inhibit?

The production of Pro-T cells

What does X-linked SCID directly inhibit?

The production of immature T cells

What does DiGeorge syndrome directly inhibit?

The production of CD8+ and CD4+

What does MHC Class II deficiency directly inhibit?

The production of CD4+

What embryologic defect causes DiGeorge syndrome?

Failed development of the 3rd and 4th pharyngeal (branchial) pouches

What immune defect occurs in DiGeorge syndrome?

T-cell deficiency due to thymic hypoplasia

What chromosome deletion is associated with DiGeorge syndrome?

22q11 deletion

What remains unaffected in DiGeorge syndrome?

B-cells and serum immunoglobulins are unaffected

Deficiency of which complement proteins predisposes to Neisseria infections?

C5-C8 deficiencies

What causes hereditary angioedema?

C1 inhibitor deficiency

• C1 activation increases vasoactive complement mediators

What causes chronic granulomatous disease (CGD)?

Defect in phagocyte oxidase enzyme

What causes leukocyte adhesion deficiency (LAD)?

Defects in integrins/selectin ligands impair leukocyte migration

What does a hereditary deficiencies in complement components increase the risk of?

Increased susceptibility to infection with pyogenic bacteria

What IF pattern is classic for lupus nephritis?

Granular immune complex deposition (“lumpy-bumpy”)

What are some congenital defects in phagocytes?

Phagocyte oxidase enzyme leading to chronic granulomatous disease (CGD)

Integrins and selectins ligands with resultant leukocyte adhesion deficiencies (LAD)

What can be the result of most genetic deficiencies of innate immunity?

Recurrent bacterial infections

What causes primary immune deficiency?

Mutations of genes involved in:

• Lymphocyte maturation

• Function

• In innate immunity

Leading to increased susceptibility to infections in early life

What is an overview of secondary immune deficiencies?

More common than primary

Found in malnutrition, infections, cancer, renal disease, or sarcoidosis

Most common cause is therapy induced suppression of the bone marrow and of lymphocyte function

What is AIDS?

A retroviral disease caused by HIV characterized by infection and depletion of CD4+ T cells and profound immunosuppression with:

• Opportunistic infections

• Secondary neoplasms

• Neurologic manifestations

What is innate immunity?

Natural immunity

Immediate

Nonspecific

Present before exposure

Which immune system uses Toll-like receptors?

Innate immune system

Used to recognize microbial molecules and molecules of damaged cells

What is adaptive immunity?

Acquired immunity

Slower initial response

Highly specific

Develops later → Strong response

Vaccination

What are the major components of innate immunity?

Epithelial barrier (skin)

Phagocytes/Macrophages

Neutrophils

NK cells

Complement proteins (plasma proteins)