Immunopathology Dr. Maysem Lec.3

AUTOIMMUNE DISEASES Autoimmunity: Immune reactions to self antigens

Autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type and result in localized tissue damage,

to multisystem diseases characterized by lesions in many organs and associated with multiple autoantibodies or T cell–mediated reactions against numerous self antigens.

Autoimmune Diseases

In many of the systemic diseases that are caused by immune complexes and autoantibodies, the lesions affect principally the connective tissue and blood vessels of the various organs involved.

Therefore, these diseases are often referred to as “collagen vascular” or “connective tissue” disorders, even though the immunologic reactions are not specifically directed against constituents of connective tissue or blood vessels.

Normal persons are unresponsive (tolerant) to their own (self) antigens, and autoimmunity results from a failure of self-tolerance.

  - Self tolerance: refers to a lack of immune responsiveness one’s own tissue antigens.

Immunologic tolerance

Central Tolerance : This refers to the process by which T and B cells that recognize self antigens are either killed (negative selection) or rendered harmless during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells).

Peripheral Tolerance Self reactive cells that escape central regulatory mechanisms can be removed or inactivated in the periphery through one of the following pathways:

1.Anergy: This term refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions. 2. suppression by regulatory T lymphocytes, 3. Activation-induced cell death ( apoptosis).

combination of inherited susceptibility genes, which influence lymphocyte tolerance, and environmental factors, such as infections or tissue injury, that alter the display of self antigens

Pathogenesis of auroimmune disaeses

Mechanisms of Autoimmunity: It is believed that the breakdown of self-tolerance and development of autoimmunity result from a

1.Genetic Factors in Autoimmunity : -Autoimmune diseases have a tendency to run in families. -Several autoimmune diseases are linked with the HLA locus, especially class II alleles (HLA-DR, -DQ) e.g. - Rheumatoid arthritis and HLA -DRB1 -Ankylosing spondylitis and HLA- B*27

-many genetic polymorphisms in ( non - HLA Genes) are associated with different autoimmune diseases. e.g. PTPN-22 gene and type I diabetes and rheumatoid arthritis.

2. Role of Infections and Tissue Injury Microbes may induce autoimmune reactions by several mechanisms: -Viruses and other microbes may share cross-reacting epitopes with self antigens,This phenomenon is called molecular mimicry. . • Microbial infections with resultant tissue necrosis and inflammation can expose self-antigens and activate APCs and lymphocytes in the tissues.  

Autoimmune diseases are , more common in women than in men.

Systemic Lupus Erythematosus(SLE): -It is a multisystem autoimmune disease caused by autoantibodies produced against numerous self-antigens and the formation of immune complexes.

-Clinically, it is an unpredictable, remitting and relapsing disease of acute or insidious onset that may involve virtually any organ in the body; mainly the skin, kidneys, serosal membranes, joints, and heart. -SLE is more common and severe in black Americans.

- Onset typically is in the second or third decade of life, but it may manifest at any age, including early childhood.

Pathogenesis of SLE: -The pathogenesis of SLE involves a combination of genetic and environmental factors and immunologic factors :

1.Genetic Factors: Familial association. Family members have an increased risk for the development of SLE. HLA association: HLA-DR2 , HLA-DR3 Other genes: Genetic deficiencies of classical pathway complement proteins, especially C1q, C2, or C4, are seen in about 10% of patients with SLE.

2.Environmental Factors. • Ultraviolet (UV) radiation (sun exposure) exacerbates the lesions of SLE. • Cigarette smoking • Sex hormones : There is a strong female preponderance (approximately 9 : 1)(female :male) It has been suggested that factors other than hormones may account for the increased risk of this disease in women.   • Drugs: such as procainamide and hydralazine can induce an SLE- like disease,

3. Immunologic factors: several components of the innate and adaptive immune system are involved in the pathogenesis of SLE. Defective elimination of self-reactive B cells, and ineffective peripheral tolerance mechanisms are most important.

Based on these clues, a model for the pathogenesis of SLE has been proposed: The fundamental defect in SLE is a failure to maintain self tolerance. Cell injury (e. g., UV and other environmental insults) leads to apoptosis and an increased burden of nuclear antigens(due to defective clearance of nuclear antigens) .

Defective B and T-cell tolerance leads to autoantibodies directed against the nuclear antigens, with the resulting immune complexes being ingested by B cells and dendritic cells; then further cellular activation, cytokine production, and augmented autoantibody synthesis, which causes more apoptosis in a self amplifying loop.

Spectrum of Autoantibodies in SLE A.Antinuclear antibodies(ANA): ANAs are directed against several nuclear antigens and can be grouped into : (1) antibodies to DNA, (2) antibodies to histones, (3) antibodies to nonhistone proteins bound to RNA, and (4) antibodies to nucleolar antigens.

-ANAs also occur in other autoimmune disorders, and in 5-15% of normal individuals . - anti-double-stranded DNA and anti-Smith antigen antibodies strongly suggest SLE.

B.Other autoantibodies: -Some directed against blood elements (i.e., red blood cells, platelets, leukocytes). - Sometimes SLE patients have (antiphospholipid antibodies).

-Some Abs bind to cardiolipin antigen, giving rise to false-positive results for syphilis. - lupus anticoagulants :

Mechanisms of Tissue Injury : 1.type III hypersensitivity Most organ damage in SLE is caused by immune complex deposition.

2. type II hypersensitivity. Autoantibodies against red cells, white cells, and platelets opsonize these cells and lead to their phagocytosis, resulting in cytopenias (autoimmune haemolytic anaemia, immune thrombocytopenia)

3-Antiphospholipids antibodies lead to increased thrombosis in patients, with varied clinical consequences, including recurrent spontaneous abortion and thrombotic episodes. These disorders are part of the antiphospholipid syndrome

4- lupus anticoagulants. Autoantibodies against clotting factors such as thrombin, and these may interfere with in vitro coagulation assays; actually exert a procoagulant effect in vivo, causing recurrent vascular thromboses, miscarriages, and cerebral ischemia

5- Autoantibodies against central nervous system receptors for various neurotransmitters have been implicated in the neuropsychiatric complications of the disease.

MORPHOLOGY: Although any organ can be involved, the most characteristic tissues affected are skin, blood vessels, kidneys, and connective tissue. -Classically, there is a type III hypersensitivity response with acute necrotizing vasculitis and fibrinoid deposits involving small arteries and arterioles. Immune complexes can be found in vessel walls.

1. Kidneys. Kidney involvement is one of the most important clinical features of SLE. Mostly it is glomerular pathology (lupus nephritis), although interstitial and tubular lesions are also seen in SLE.

2. Skin: Malar erythema is the classic lesion (butterfly rash) , Exposure to sunlight (UV light) exacerbates the erythema (so-called photosensitivity)   3. Joints: There is synovitis. 4. CNS. Central nervous system (CNS) involvement 5. Spleen , Lungs , heart

Disease manifestations -It typically presents insidiously as a systemic, chronic, recurrent, febrile illness with symptoms referable to virtually any tissue but especially joints, skin, kidneys, and serosal membranes.

-Autoantibodies to hematologic components may induce thrombocytopenia, leukopenia, anemia. -neurologic abnormalities with focal neurologic deficits and/or neuropsychiatric symptoms -

The most common causes of death are renal failure, intercurrent infections, and cardiovascular disease.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that affects mainly the joints, especially small joints ( (digits before wrist, ankles, elbows, and knees) in a bilaterally symmetric pattern), but can affect multiple tissues (blood vessels, skin, heart, lungs, and muscles)

RA is caused by an autoimmune response against self-antigen(s), which leads to T cell reactions in the joint with production of cytokines that activate phagocytes that damage tissues and stimulate proliferation of synovial cells (synovitis).

Antibodies may also contribute to the disease Antibodies may also contribute to the disease. About 80% of patients have serum immunoglobulin M (IgM) (and, less frequently, IgA) autoantibodies that bind to the Fc portions of their own (self ) IgG..

These autoantibodies are called rheumatoid factor These autoantibodies are called rheumatoid factor. They may form immune complexes with self-IgG that deposit in joints and other tissues, leading to inflammation and tissue damage.

Sjogren syndrome It is characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), resulting from immune-mediated destruction of the lacrimal and salivary glands.

It occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease (secondary form).

Most patients have rheumatoid factor without having rheumatoid arthritis; ANAs against ribonucleoproteins SS-A (Ro) and SS-B (La) are especially common

The disease is believed to be caused by an autoimmune T cell reaction against one or more unknown self antigens expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues.  

Systemic Sclerosis (Scleroderma) (SS) It is is an immunologic disorder characterized by excessive fibrosis in multiple tissues, obliterative vascular disease, and evidence of autoimmunity, mainly the production of multiple autoantibodies.

The distinctive feature of SS is the striking cutaneous involvement The distinctive feature of SS is the striking cutaneous involvement. Cutaneous involvement is the usual presenting manifestation and eventually appears in approximately 95% of cases

The visceral involvement—of the gastrointestinal tract, lungs, kidneys, heart, and skeletal muscles—is responsible for most of the related morbidity and mortality.

scleroderma

Almost all patients exhibit Raynaud phenomenon, a vascular disorder characterized by reversible vasospasm of the arteries. Typically the hands turn white on exposure to cold, reflecting vasospasm, followed by change to blue as ischemia and cyanosis develop. Finally, the color changes to red as reactive vasodilation occurs

Raynaud phenomenon

- SS affects women three times more often than men, with a peak incidence in the 50- to 60-year age group.

SS can be classified into two groups on the basis of its clinical course: -1-Diffuse scleroderma, characterized by initial widespread skin involvement, with rapid progression and early visceral involvement 2- Limited scleroderma, with relatively mild skin involvement, often confined to the fingers and face. Involvement of the viscera occurs late.

This clinical presentation is also called the CREST syndrome because of its frequent features of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.

IMMUNE DEFICIENCY DISEASES: 1.Primary immunodeficiencies are usually hereditary and manifest between 6 months and 2 years of life . 2. Secondary immunodeficiencies result from altered immune function due to infections e.g. Acquired Immunodeficiency Syndrome (AIDS), malnutrition, aging, immunosuppression, irradiation, chemotherapy, or autoimmunity.

-Clinically, patients with immune deficiency present with increased susceptibility to infections as well as to certain forms of cancer.

The type of infections in a given patient depends largely on the component of the immune system that is affected:

- Patients with defects in immunoglobulin, complement, or phagocytic cells typically suffer from recurrent infections with pyogenic bacteria. -Those with defects in cell-mediated immunity are prone to infections caused by viruses, fungi, and intracellular Bacteria

Primary immunodeficiencies (Congenital) Caused by mutations in genes involved in lymphocyte maturation or function, or in innate immunity • Some of these disorders are :

1.X-Linked Agammaglobulinemia(XLA) Bruton Disease is characterized by the failure of pre-B cells to differentiate into B cells and, there is a resultant absent or markedly decreased numbers of B cells in the circulation, with depressed serum levels of all classes of immunoglobulins. Normal T cell–mediated responses

-XLA does not become apparent until the affected infant reach the age of approximately 6 months. In most cases, recurrent bacterial infections such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis.

2.Common Variable Immunodeficiency -Is a heterogeneous group of disorders characterized by hypogammaglobulinemia, impaired antibody responses to infection (or vaccination), and increased susceptibility to infections.

The clinical manifestations are superficially similar to those of XLA, but in common variable immunodeficiency, males and females are affected equally and the onset of symptoms is much later, in the second or third decade of life

3.Isolated IgA Deficiency The most common of all the primary immune deficiency diseases -Absent serum and secretory IgA - IgA is the major immunoglobulin in mucosal secretions and is thus involved in defending the airways and the gastrointestinal tract.

Although most people with this condition are asymptomatic, weakened mucosal defenses predispose patients to recurrent sinopulmonary infections and diarrhea. -There is also a significant (but unexplained) association with autoimmune diseases.

Hyper-IgM Syndrome Patients with the hyper-IgM syndrome produce normal (or even supranormal) levels of IgM antibodies to antigens but lack the ability to produce the IgG, IgA, and IgE isotypes; the underlying defect is an inability of T cells to induce B cell isotype switching. In 70% of patients, the disease is X-linked

Other primary immunodeficiency diseases include: -Severe Combined Immunodeficiency -Thymic Hypoplasia: DiGeorge Syndrome - Wiskott-Aldrich Syndrome :Immune Deficiency with thrombocytopenia and Eczema. -Genetic Deficiencies of Complement Protein -Defects in Lymphocyte Activation -Defect in phagocyte