Chapter 6 part (Dr. Guervin) TEST 2 Flashcards
Autoimmune Diseases
• Affect at least 1-2% of the US population; Women»_space;> Men
• Presence of AUTOANTIBODIES ≠ AUTOIMMUNE Disease
– Autoantibodies can be found in normal individuals (more common as we age)
– Autoantibodies can be produced after damage to tissues
• Pathologic Autoimmunity “CONFIRMED” when:
– Presence of an immune reaction specific for some Self Antigen or Self Tissue
– Evidence that such a reaction is NOT Secondary to tissue damage but is of PRIMARY Pathogenic significance
– Absence of another well-defined cause of the disease
• Immune-Mediated Inflammatory Diseases:
– Disorders in which chronic inflammation is a prominent component
– Maybe autoimmune, or the immune response may be DIRECTED AGAINST Normally harmless microbes such as Gut commensal bacteria
Autoimmune Disease Examples
ORGAN SPECIFIC:
- Autoimmune Hemolytic Anemia
- Autoimmune Thrombocytopenia
- Autoimmune Atrophic Gastritis of Pernicious Anemia
- Myasthania Gravis
- Graves Disease
- Goodpasture Syndrome
- Diseases Mediated by T Cells
- Type 1 Diabetes Mellitus
- Multiple Sclerosis
- Inflammatory Bowel
SYSTEMIC:
- Systemic Lupus Erythematosus
- Rheumatoid Arthritis
- Systemic Sclerosis
- Sjörgen Syndrome
- Polyarteritis Nodosa
Autoimmune Disease Manifestations
• Vary widely
• Organ-specific disease
– Type 1 Diabetes MELLITUS - β cells of the Pancreatic
Islets
– Multiple Sclerosis – CNS myelin
• Systemic or Generalized Disease
– SLE - diversity of ANTIBODIES directed against DNA, Platelets, Red cells, and Protein-Phospholipid complexes
Immunologic Tolerance
• Process where immune system learns to “tolerate” an antigen
– SELF- TOLERANCE
• Lymphocyte receptors are generated by Random
SOMATIC RECOMBINATION of genes
– Receptors capable of Recognizing SELF Antigens are generated constantly
– These cells MUST BE ELIMINATED or Inactivated as soon as they recognize self antigens
• 2 types:
– CENTRAL tolerance: thymus and bone marrow
– PERIPHERAL tolerance
Central Tolerance- T Cells
• During development, many T cells that express HIGH-AFFINITY TCR’s for self antigens are produced
• “NEGATIVE SELECTION” or “DELETION”– Immature Lymphocytes encounter antigens in the thymus, many die by APOPTOSIS
– Even Peripheral tissue antigens which are processed and presented by thymic antigen-presenting cells
• Some CD4 + T Cells that see self antigens in the thymus DO NOT DIE but DEVELOP into REGULATORY T cells
Central Tolerance- B Cells
• B cells that STRONGLY Recognize Self Antigens in the Bone Marrow:
– Many reactivate the machinery of antigen RECEPTOR Gene REARRANGEMENT and express NEW Antigen Receptors
***** Called “RECEPTOR EDITING”
– If Receptor Editing does not occur, the self-reactive cells Undergo APOPTOSIS
Peripheral Tolerance- ANERGY
• Lymphocytes that recognize self antigens are rendered Functionally UNRESPONSIVE
– Happens when the antigen presented to T cells by APC in periphery GETS NO/ WEAK COSTIMULATORY Molecule Expression
i) Some Tumors and Viruses may use the same pathways of immune regulation to EVADE immune attack
– B cells encounter Self Antigen in peripheral tissues, and in in the ABSENCE of specific Helper T Cells, the B cells become UNABLE TO RESPOND to subsequent antigenic stimulation
Peripheral Tolerance- Suppression by Regulatory T Cells
- REGULATORY T Cells function to PREVENT Immune reactions against Self Antigens
- Mechanisms by which they SUPPRESS Immune Responses are not fully defined
• May play a role in the ACCEPTANCE of the FETUS
– Fetus expresses Paternal Antigens that are foreign to the mother yet have to be tolerated
– Defects in this may lead to recurrent spontaneous ABORTIONS
Peripheral Tolerance- Deletion/ Apoptosis
• T cells that recognize Self Antigens may receive signals that → Death by APOPTOSIS
Immune-Privilege Sites
• Some Antigens are hidden (sequestered) from the immune system
– Do not communicate with the blood and lymph
• E.g. TESTIS, EYES, and BRAIN
• If the antigens of these tissues are released after trauma or infection
– Can → PROLONGED Tissue Inflammation and Injury
Mechanisms of Autoimmunity: General Principles
- Breach of the normal equilibrium of Lymphocyte Activation and Tolerance Mechanisms
- COMBINATION of Genetic Susceptibility and Environmental Triggers
Changes that Contribute to the Development of Autoimmunity
- DEFECTIVE Tolerance or Regulation
- ABNORMAL Display of Self Antigens
- INFLAMMATION or an INITIAL Innate Immune Response
Role of Infection
1) Induction of Costimualtors on APCs:
- Leads to activation of APC —> Self Reactive T Cell
2) Molecular Mimicry:
- Leads to SELF-REACTIVE T Cells that also Recognizes Microbial Peptide
Role of Infection Cont
• Classic Example of molecular MIMICRY is RHEUMATIC HEART DISEASE!!!!!!!!
– Antibodies against STREPTOCOCCAL Proteins CROSS-REACT with MYOCARDIAL PROTEINS and cause MYOCARDITIS
• Some Viruses (e.g., EBV and HIV) cause POLYCLONAL B-cell Activation that can → Production of AUTOANTIBODIES
Infections May Protect Against Some Autoimmune Diseases
- Incidence of Autoimmune Diseases is INCREASING in developed countries
- Infections are better Controlled
- In some animal models (e.g., of type 1 diabetes) infections greatly reduce the incidence of disease
- Possibility because infections PROMOTE Low-Level IL-2 Production, and this is essential for MAINTAINING Regulatory T cells!!!
Micro biome and Autoimmune Diseases
- Normal Gut and Skin Microbiome Influences the DEVELOPMENT of Autoimmunity
- Different Non-Pathogenic microbes affect the relative proportions of Effector and Regulatory T cells, and SHAPE THE HOST RESPONSE towards or away from Aberrant Activation
General Features of AI Disease
- Typically CHRONIC
- Sometimes has RELAPSES and REMISSIONS
- Damage is often PROGRESSIVE
• Can get “EPITOPE SPREADING”
– Immune response against One Self Antigen → Tissue Damage →
release of other Antigens → ACTIVATION of Lymphocytes
• Some AI diseases are caused by Autoantibodies, but MOST are CAUSED BY Abnormal and Excessive TH1 and TH17 responses!!!!!!!!!!!
• Systemic Diseases tend to involve blood vessels and Connective Tissues
– “COLLAGEN VASCULAR” or ”Connective Tissue” diseases
Systemic Lupus Erythematosus (SLE)
- ~1 in 2,500; Women»_space; Men
- African American and Hispanic > Whites
• Autoimmune disease Involving MULTIPLE Organs
– Especially skin, joints, kidney, and serial membranes
- Multiple Autoantibodies, particularly ANTINUCLEAR ANTIBODIES (ANAs)
- Injury is caused mainly by Deposition of Immune Complexes and binding of antibodies to various cells and tissues
- Onset can be Acute or Insidious
- Typically a Chronic, Remitting and Relapsing
- The Clinical Presentation is HIGHLY VARIABLE
Criteria for Classification of SLE
“BRAIN SOAP MD”
B: Blood Hematologic Disorder - Hemolytic Anemia - Leukopenia - Lymphopenia _ Thrombocytopenia
R: Renal Disorder
- Proteinuria
- Cellular Casts
A: Arthritis
I: Immunologic Disorder
- Anti-DNA Abs
- Anti-Sm Abs!!!!!!
N: Neurologic Disorder:
- Seizures
- Psychosis
S: Serositis
- Pericarditis
- Pleuritis
O: Oral Ulcers
A: Antinuclear Ab
- ANA
P: Photosensitivity
- Unusual reaction to Light (UV)
M: Mala Rash
- “Butterfly”
D: Discoid Rash
- Scaling, atrophic Scarring
Antibodies in Systemic Autoimmune Diseases
* All have ANA!!!!!!!***
Antinuclear Antibodies (ANAs)
• Directed AGAINST Nuclear Antigens
• 4 categories:
1) Antibodies to DNA
2) Antibodies to HISTONES
3) Antibodies to Nonhistone Proteins BOUND to RNA
4) Antibodies to NUCLEOLAR ANTIGENS
Detecting ANAs
- INDIRECT Immunofluorescence
- 4 basic PATTERNS of Immunofluorescence:
- Diffuse
- Anti-Centromeric
- Nucleolar
- Speckled
• Pattern can suggest specific diseases, but it’s not absolutely specific
– Antibodies to Double-Stranded DNA and the so- called SMITH (Sm) Antigen are virtually diagnostic of SLE!!!!!!!!!!!!!!!!
Antiphospholipid Antibodies
- ~30-40% of lupus patients
- May cause a FALSE-POSITIVE Test RESULT (VDRL) for SYPHILIS!!!!!!!!!
• Can interfere with Clotting Tests, such as partial thromboplastin time (PTT)!!!!!!
– “Lupus anticoagulant”
– HYPERCOAGULABLE state!!!!
Etiology and Pathogenesis of SLE
• Failure of the mechanisms that maintain self- tolerance
– Cause is unknown
• Thought to involve Genetic and Environmental factors
Genetic Factors in SLE
• Evidence to support a Genetic Predisposition:
A) INCREASED risk of SLE in family members of patients with SLE
B) HIGHER RATE of CONCORDANCE (>20%) in MONOZYGOTIC TWINS compared to dizygotic twins (1-3%)
C) Specific alleles of the HLA-DQ locus have been linked to the production of Anti–Souble-Stranded DNA, anti-Sm, and anti- phospholipid antibodies
D) Some Lupus patients have inherited deficiencies of early complement components → IMPAIRED REMOVAL of Circulating Immune Complexes
• Multiple MHC and non-MHC genes Implicated
• Many Susceptibility loci encode proteins involved in
lymphocyte signaling and interferon responses
– Relative risk for each locus is small
Environmental Factors in SLE
• Exposure to ULTRAVIOLET (UV) LIGHT:
– EXACERBATES the Disease in many individuals
– UV Irradiation may INDUCE APOPTOSIS in cells and may ALTER the DNA in such a way that it becomes Immunogenic
– UV light may also STIMULATE Keratinocytes to produce IL-1 → inflammation!!!!!!!!!
• Gender bias:
– Sex hormones and genes on the X Chromosome
• Drugs:
– Hydralazine, procainamide, and D-penicillamine
• Microbiome?
– “The microbiome–systemic diseases connection”
Morphology in SLE
• BLOOD VESSELS:
– An acute NECROTIZING VASCULITIS involving capillaries, small arteries and arterioles
• JOINTS:
– NON-EROSIVE Synovitis with little deformity!!!!!
(opposite of rheumatoid arthritis)
• KIDNEYS!!!!!!!!!
Kidneys in SLE
• Up to 50% of SLE patients have clinically significant Renal Involvement!!!!!
• All of the GLOMERULAR Lesions are the result of Immune Complex Deposition
– Both in situ formation and deposition of preformed circulating immune complexes
Kidneys Cont in SLE
• 6 patterns of glomerular disease (reasons for different patterns in unknown): 1) Minimal mesangial lupus nephritis (class I): see on EM only (LEAST COMMON)
2) Mesangial proliferative lupus nephritis (class II)
3) Focal lupus nephritis (class III): less than 50%
4) DIFFUSE LUPUS NEPHRITIS (MOST COMMON and Most Severe)!!!!!!!!!!!!!!!!!!!
Skin in SLE
- Characteristic “BUTTERFLY” rash ~ 50% of patients
- Can have a similar rash on extremities and trunk
- EXPOSURE to SUNLIGHT incites or accentuates the erythema
• Immunofluorescence: deposition of immunoglobulin and complement along the DERMAL-EPIDERMAL JUNCTION!!!!!!!!!
– Can be present in Uninvolved skin
– Also seen in Scleroderma or Dermatomyositis
Pericarditis and Other Serial Involvement in SLE
• Inflammation of the serosal lining membranes may be acute, subacute, or chronic
• ACUTE
– Mesothelial surfaces are sometimes covered with
FIBRINOUS EXUDATE
• LATER
– Thickened, opaque, and coated with a SHAGGY FIBROUS TISSUE!!!
– May lead to partial or total obliteration of the serial cavity
• Pleural and Pericardial EFFUSIONS may be Present
Cardiovascular System in SLE
- ANY LAYER of the Heart can be Damaged
- Symptomatic or Asymptomatic pericardial involvement ~50% of the time
- MYOCARDITIS (inflammation of the myocardium) can → Tachycardia and Electrocardiographic Abnormalities
- CORONARY Artery Disease (angina, myocardial infarction)
- VALVULAR Abnormalities, primarily of the MITRAL and AORTIC VALVES→ STENOSIS and/or REGURGITATION
• Valvular (a.k.a. LIBMAN-SACKS) Endocarditis
– Uncommon now b/c of steroids
– NONBACTERIAL Verrucous Endocarditis!!!!!!
Other Organs
• CENTRAL NERVOUS SYSTEM:
– Neuropsychiatric symptoms
i) Non-inflammatory occlusion of small vessels
ii) May be due to endothelial damage by Autoantibodies or Immune Complexes
• SPLEEN:
– SPLENOMEGALY, Capsular Thickening, and Follicular Hyperplasia
• LUNGS:
– Pleuritis and Pleural Effusions ~ 50% of patients
– Chronic Interstitial Fibrosis and secondary Pulmonary Hypertension
Clinical Features of SLE
- Most typically YOUNG WOMEN
- Presentation can be overt or Subtle and Puzzling
- ANAs found in virtually 100% of patients, but not specific for SLE!!!!
• May have signs of RENAL INVOLVEMENT:
– HEMATURIA, Red Cell Casts, Proteinuria, and in some cases the classic NEPHROTIC SYNDROME
• INCREASED numbers of Infections
– Due to underlying Immune dysfunction and treatment with Immunosuppressive Drugs
- Course of the disease is variable and unpredictable
- Disease flares typically treated with corticosteroids or other immunosuppressive drugs
• Causes of DEATH include:
– Renal Failure, Infections, and Coronary Artery Disease
Chronic Discoid Lupus Erythematosus
- Primarily skin manifestations; rarely systemic manifestations
- Skin plaques showing varying degrees of Edema, Erythema, SCALINESS, Follicular Plugging, and Skin ATROPHY surrounded by an Elevated Erythematous border
- Usually FACE and SCALP, but can occur anywhere
Subacute Cutaneous Lupus Erythema
• Presents with predominant skin involvement
• Distinguished from chronic discoid LE by:
– Skin rash tends to be WIDESPREAD, SUPERFICIAL, and NON-SCARRING
• Most patients have MILD SYSTEMIC Symptoms consistent with SLE
Drug-Induced Lupus Erythematosus
- LE-like syndrome may develop in patients receiving a variety of drugs
- E.g. Hydralazine, Procainamide, Isoniazid, and D- Penicillamine
- Also ANTI-TNF therapy!!!!!!! (used to treat Rheumatoid Arthritis and other autoimmune diseases)
- Affects Multiple Organs, but Renal and Central Nervous System involvement is uncommon
- Disease REMITS after WITHDRAWAL of the offending drug
Sjörgen Syndrome
• CHRONIC disease
• Characterized by:
– DRY EYES (keratoconjunctivitis sicca)
– DRY MOUTH (xerostomia)
• From Immunologically mediated DESTRUCTION of the LACRIMAL and SALIVARY Glands
– Lymphocyte infiltration and eventual FIBROSIS
• Can occur on it’s Own or in Association with another autoimmune disease (~60%)
Clinical Features of Sjörgen Syndrome
• Typically seen in women, aged 50-60
• KERATOCONJUNCTIVITIS:
– Blurring of Vision, Burning, and Itching
• XEROSTOMIA:
– Difficulty in SWALLOWING Solid Foods, a Decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa
• Can Also Have:
– PAROTID GLAND ENLARGMENT
– DRYNESS of the Nasal Mucosa and Epistaxis
– Recurrent Bronchitis and Pneumonitis
– Synovitis
– Diffuse Pulmonary Fibrosis
– PERIPHERAL Neuropathy
– RENAL: Renal Tubular Acidosis, Uricosuria, and Phosphaturia
Pathology of Sjörgen Syndrome
• Biopsy of the lip (to examine minor salivary glands) is essential for the diagnosis of Sjögren syndrome
• Intense lymphocytic response in the tissues that are involved:
– EARLY: MIXTURE of Polyclonal T and B cells
– OVER TIME: a Dominant B-cell clone can emerge → Marginal Zone LYMPHOMA (~5%)
Systemic Sclerosis (Scleroderma)
• CHARACTERIZED BY:
– CHRONIC Inflammation thought to be the result of autoimmunity
– Widespread DAMAGE to Small Blood Vessels
– Progressive Interstitial and Perivascular FIBROSIS in the Skin (EARLY) and Multiple organs
a) E.g. GI tract, kidneys, heart, muscles, and lungs
• Majority Progress with DEATH from Renal Failure, Cardiac
Failure, Pulmonary Insufficiency, or Malabsorption
– DIFFUSE Scleroderma: Widespread Skin Involvement at onset, with RAPID progression
– LIMITED Scleroderma: Skin involvement is often CONFINED to Fingers, Forearms, and Face, with visceral involvement LATE
Etiology and Pathology of Scleroderma
• Cause of systemic sclerosis is unknown
• Thought to be related to:
– Autoimmunity
– Vascular damage
– Fibrosis
Clinical Fearures of Scleroderma
- Female-to-Male ratio of 3 : 1
- Peak incidence in the 50-60-year age group
- Striking Cutaneous Changes (skin thickening)
• RAYNAUD PHENOMENON
– Episodic Vasoconstriction of the Arteries and Arterioles of the Extremities
– Seen in virtually ALL Patients and precedes other symptoms in 70% of cases
- DYSPHAGIA from ESOPHAGEAL FIBROSIS → HYPOMOTILITY
- Respiratory Difficulty
- Myocardial Fibrosis → Arrhythmias or Cardiac failure
• RENAL:
– Mild Proteinuria
– Malignant Hypertension
CREST Syndrome associated with Scleroderma
• Some patents with limited Scleroderma
• COMBINATION of: – Calcinosis – Raynaud phenomenon – Esophageal Dysmotility – Sclerodactyly – Telangiectasia
Mixed Connective Tissue Disease
• A disease with Clinical Features that are a MIXTURE of the features of SLE, systemic sclerosis, and polymyositis
• Suggested that “Mixed Connective Tissue Disease” is NOT a Distinct Entity
– Rather different patients represent subsets of SLE, systemic sclerosis, and polymyositis
– Disease can (but not always), Evolve into classic SLE or systemic sclerosis
• SERIOUS complications:
– PULMONARY HYPERTENSION, INTERSTITIAL Lung Disease, and Renal Disease
IgG4 Related Disease
- Relatively new entity
- Most often affects MIDDLE-Aged and OLDER MEN
- 1st characterized in AUTOIMMUNE PANCREATITIS!!!!!!
• Now reported in virtually ALL Organs
– Mikulicz Syndrome (enlargement and fibrosis of Salivary and Lacrimal glands), Riedel Thyroiditis, Idiopathic Retroperitoneal Fibrosis, and Inflammatory Pseudotumors of the Orbit, Lungs, and Kidneys
• Characterized by:
– Tissues are infiltrated by IgG4 Antibody - producing Plasma cells and Lymphocytes (mainly T cells)
– STORIFORM Fibrosis
– Obliterative Phlebitis
– Usually INCREASED Serum IgG4!!!!!!!!
• Pathogenesis Unknown and unclear if it’s really autoimmune
Rejection of Tissue Transplant
- Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and DESTROY Tissue Grafts
Recognition of Graft Alloantigens by T and B Lymphocytes
• Major ANTIGENIC Differences between a Donor and Recipient are differences in HLA alleles
– HLA genes are highly POLYMORPHIC, so there are always some differences between individuals (except identical twins)
– Recipient’s T cells RECOGNIZE Donor Antigens from the GRAFT
- ALLOGRAFTS: SAME Species
- XENOGRAFTS: rafts from One Species to Another
Recognition of Alloantigens in Organ Grafts:
DIRECT Pathway:
- Donor APC in the Graft activates CD4+ and CD8+ T Cells
INDIRECT Pathway:
- Recipient’s APC activated ONLY CD4+ T Cells!!!!!
T Cell- Mediated Reactions in Grafts
• ACUTE REJECTION:
– Most commonly seen within the INITIAL MONTHS after transplantation
– Clinical and Biochemical signs of Organ Failure
– CYTOKINES secreted by Activated CD4+ T cells
– Increased VASCULAR PERMEABILITY and local accumulation of Mononuclear Cells (lymphocytes and macrophages)
• CHRONIC REJECTION:
– LYMPHOCYTES react against Alloantigens in the Vessel
Wall
– Secrete CYTOKINES that Induce Local Inflammation
Antibosy-Mediated Reactions in Grafts
• HYPERACUTE REJECTION:
– Occurs when PREFORMED Antidonor antibodies are present in the Circulation of the Recipient
– Can develop in Persons with: PREVIOUS Transplant, PRIOR Blood Transfusions, and MULTIPARIOUS Women
– Cross-Matching now makes this very rare
• ACUTE ANTIBODY-MEDIATED REJECTION:
– ANTIDONOR Antibodies produced after transplantation
– Initial TARGET of these antibodies seems to be the GRAFT VASCULATURE!!!!!!
• CHRONIC ANTIBODY-MEDIATED REJECTION:
– Usually develops Insidiously
– Primarily AFFECTS Vascular Components
Methods of Increasing Graft Survival
• HLA MATCHING:
– In KIDNEY transplants: substantial benefit if all the polymorphic HLA alleles are matched (both inherited alleles of HLA-A, -B, and DR)!!!!!!!!!!!
– Not done for transplants of Liver, Heart, and Lungs
• IMMUNOSUPPRESSIVE THERAPY (necessary but increased risk of infections)
– STEROIDS (which reduce inflammation)
– Mycophenolate mofetil (which INHIBITS Lymphocyte proliferation)
– TACROMILUS (FK506)- INHIBITS T Cell Functions!!!!!!!!
- T CELL and B CELL DEPLETING ANTIBODIES
- Pooled INTRAVENOUS IgG (IVIG): SUPPRESSES Inflammation by unknown mechanisms
- PLASMAPHERESIS: used in cases of SEVERE Antibody-Mediated Rejection
Immunosuppression and Infection
• POLYOMA VIRUS:
– Can REACTIVATE, Infect Renal Tubules and may even cause graft failure
• INCREASED RISK for Developing (from re-activation of latent viruses):
– EBV-induced LYMPHOMAS!!!!!
– Human Papillomavirus (HPV)-induced Squamous Cell
CARCINOMAS!!!!!
– Kaposi Sarcoma (HHV8)!!!!!!
• Any OPPORTUNISTIC Infection
Transplantation of Other Solid Organs
- KIDNEY was the FIRST and is the MOST Frequently Transplanted organ
- Also Liver, Heart, Lungs, and Pancreas
Transplantation of Hematopoietic Stem Cells- Bone Marrow Transplant
• USED FOR:
– Hematologic Malignancies
– Bone Marrow Failure Syndromes (such as aplastic anemia)
– Inherited Stem Cell Defects (such as sickle cell anemia, thalassemia, and immunodeficiency states)
• Usually Harvested from Peripheral blood after they are MOBILIZED from the Bone Marrow by administration of HEMATOPOIETIC Growth Factors
– Can also be obtained from umbilical cord blood of newborn infants
• Most of the time, the recipient is IRRADIATED or Treated with high doses of Chemotherapy to DESTROY the Immune system then allowing the transplanted Stem Cells to ENGRAFT
Graft vs Host Disease (GVHD)
• Occurs when Immunologically COMPETENT Cells or their precursors are transplanted into immunologically crippled recipients
– The transferred cells RECOGNIZE Alloantigens in the host and attack host tissues
- Seen most commonly in the setting of HSC TRANSPLANTATION!!!!!!!!
- RARELY Occurs following Transplantation of SOLID Organs rich in lymphoid cells (e.g., the liver) or Transfusion of unirradiated blood
- To minimize GVHD HLA-matching is CRITICAL!!!!!!!!
Acute GVHD
• Within DAYS to WEEKS after allogeneic bone marrow Transplantation
• ANY Organ may be affected, but the majority of clinical manifestations from:
– Immune system, skin, liver, and intestines
Chronic GVHD
- May follow the acute syndrome or may occur insidiously
- EXTENSIVE Cutaneous injury
- CHRONIC Liver disease
- Damage to the gastrointestinal tract may cause esophageal strictures
• The Immune System is devastated, with INVOLUTION of the THYMUS and Depletion of Lymphocytes in the Lymph Nodes
– Recurrent and life-threatening infections
• Some patients develop MANIFESTATIONS of Autoimmunity
GVHD
• Mediated by T lymphocytes CONTAINED in the Transplanted DONOR CELLS
– So DEPLETION of DONOR T CELLS before transfusion virtually eliminates the disease
• Unfortunately Depletion of Donor T Cells leads to:
– RECURRENCE of Tumor in leukemic patients
i) Deliberate Induction of Graft-Versus-Leukemia effect by infusion of allogeneic T cells
– Increased INDIGENCE of Graft FAILURES
– Increased RATES of EBV-related B-cell LYMPHOMA!!!!!!
Immunodeficiency after BMT
• Can be from:
– Prior treatment
– MYELOABLATIVE Preparation for the graft
– DELAY in REPOPULATION of the recipient’s immune
system
– ATTACK ON the Host’s Immune cells BY GRAFTED Lymphocytes
• Profoundly IMMUNOSUPPRESSED:
– Any infection
– Re-activation of CMV especially bad
Immunodeficiency Syndromes
INCREASED Infections:
- Newly Acquired or Reactivation of latent infections
Primary (Congenital) Syndromes
• Usually detected between 6 Months and 2 Years of life
– Susceptible to RECURRENT Infections
• Defects in INNATE Immunity
– Typically affect LEUKOCYTE Functions or the COMPLEMENT System
• Defects in ADAPTIVE Immunity
– Abnormalities in Lymphocyte Maturation or Activation
Severe Combined Immunodeficiency (SCID)
• Defects in BOTH Humoral and Cell-mediated immune responses
• INFANTS Present with:
– Prominent THRUSH (oralcandidiasis) – Extensive Diaper Rash
– Failure to Thrive
• Some infants develop GVHD (rash)
– Maternal T cells are TRANSFERRED ACROSS the Placenta and attack the fetus
• Extremely susceptible to RECURRENT, Severe infections:
– Candida albicans, Pneumocystis jiroveci, Pseudomonas, CMV, Varicella, and a whole host of bacteria
• Without HSC (BMT) transplantation, death OCCURS WITHIN the FIRST YEAR of life
– Gene therapy may also be possible
- X-linked – MOST COMMON!!!!!!
- Autosomal recessive disorders
X Linked Agammaglobulinemia (Bruton Agammaglobulinemia)
• FAILURE of B-cell precursors (pro-B cells and pre-B cells) to DEVELOP into MAUTRE B cells
– B cells are ABSENT or markedly DECREASED in the circulation
– Serum Levels of ALL Classes of IMMUNOGLOBULINS are DEPRESSED
– Plasma cells are ABSENT throughout the body
– T cell–mediated reactions are NORMAL!!!!!!!
• Usually becomes Apparent after ~6 months of age
– When MATERNAL Immunoglobulins are DEPLETED
• INFECTIONS (ones that rely on antibodies to clear them):
– Recurrent bacterial Infections of the RESPIRATORY Tract
• Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus
– Viruses in the bloodstream or mucosal secretions
• ENTEROVIRUSES, such as echovirus, poliovirus, and coxsackievirus
– Giardia lamblia (intestinal protozoan)
X- Linked Agammaglobulinemia (Bruton Agammaglobulinemia) CONT
• ~35% develop AUTOIMMUNE Diseases (like arthritis and dermatomyositis)
– Likely from the BREAKDOWN of Self-Tolerance
– Chronic infections may also play a role
• TREATMENT:
– REPLACEMENT Therapy with Immunoglobulins (IVIG)
DiGeorge Syndrome (Thymic Hypoplasia)
• T-cell DEFICIENCY!!!!!!
• Results from FAILURE of Development of the THIRD and FOURTH Pharyngeal pouches
– Gives rise to:
A) THYMUS:
– Loss of T Cell-Mediated Immunity
– Poor defense against certain Fungal and Viral infections
B) PARATHYROIDS:
– Hypocalcemia→TETANY
C) Some of the C cells of the thyroid
D) Ultimobranchial body
– Congenital defects of the heart and Great Vessels
– May also have ABNORMAL appearance of the Mouth, Ears, and facies
• Considered a component of the 22q11 DELETION SYNDROME!!!!!!!!!!!!!!!!!!!
Hyper- IgM Syndrome
- Pts make IgM antibodies can’t produce IgG, IgA, and IgE antibodies
- From DEFECT IN ability of HELPER T Cells to DELIVER Activating signals to B cells and macrophages
- X-LINKED (70%) or AUTOSOMAL RECESSIVE
- Pts Present with RECURRENT PYOGENIC infections
- Those with CD40L mutations also Susceptible to Pneumocystis jiroveci PNEUMONIA
- Occasionally, IgM antibodies react with blood cells → Autoimmune Hemolytic Anemia, Thrombocytopenia, and Neutropenia
Common Variable Immunodeficiency (CVID)
• Group of disorders with HYPOGAMMAGLOBULINEMIA
– Usually ALL Antibody classes; sometimes only IgG
– Diagnosis REQUIRES EXCLUSION of other diseases
• SPORADIC and Inherited forms
• Have Normal/Near-Normal NUMBERS of B cells (as
opposed to X-linked Agammaglobulinemia)
– But they ARENT able to DIFFERENTIATE into Plasma cells
• Clinically Resembles X-linked agammaglobulinemia
– Although M = F; Childhood or Adolescence
Isolated IgA Deficiency
- Fairly common: ~1 in 600 of European descent
- Extremely LOW LEVELS of both serum and secretory IgA
- Familial or acquired in association with toxoplasmosis, measles, or some other viral infection
- Most Asymptomatic
• Symptomatic patients
– Recurrent Sinopulmonary Infections and Diarrhea
• Pts have a HIGH Frequency of Respiratory Tract Allergy and Autoimmune Diseases (esp. SLE and rheumatoid arthritis)
• Pts transfused with IgA-Containing Blood
– Can develop Severe/Fatal, ANAPHYLACTIC Reactions, because the IgA behaves like a foreign
Immunodeficiencies Associated with Systemic Diseases
• WISKOTT- ALDRICH Syndrome:
– X-linked
– Thrombocytopenia, eczema, and recurrent infection → EARLY DEATH
– TREATMENT: HSC TRANSPLANTATION
• ATAXIA TELANGIECTASIA:
– Autosomal-Recessive
– ABNORMAL GAIT (ataxia), Vascular Malformations (telangiectasia), Neurologic Deficits, increased incidence of Tumors, and Immunodeficiency
Secondary (Acquired) Immunodeficiency
- Cancer, diabetes and other metabolic diseases
- Complications of cancers
• INFECTIONS
– Acquired Immunodeficiency Syndrome (AIDS)
- Malnutrition
- Immunosuppressive therapy
- IRRADIATION
- Chemotherapy for Cancer and other Diseases
Acquired Immunodeficiency Syndrome (AIDS)
- Caused by the Human Immunodeficiency Virus (HIV) – a RETROVIRUS!!!!!!!!!
- Characterized by Profound IMMUNOSUPPRESSION → Opportunistic Infections, Secondary Neoplasms, and Neurologic Manifestations
• By end of 2009 in US: > 1 million cases of AIDS had been reported
– Ages 25-44:
i) 2nd leading cause of DEATH in men and the 3rd for women
- Global – Heavy BURDEN in Africa and Asia
- Rates of NEW Infections is DECREASING
Modes of HIV Transmission
• SEXUAL TRANSMISSION:
– Accounts for > 75% of all cases of HIV transmission
– ENHANCED by coexisting STDs!!!!!!!!!!!
• PARENTAL TRANSMISSION:
– IV Drug Abusers
– Hemophiliacs who received factor VIII and factor IX concentrates
– Recipients of blood transfusion
i) Virtually Eliminated (current risk 1 in > 2 million) due to:
a) SCREENING of Donated Blood and plasma for antibody to HIV
b) Stringent PURITY criteria for factor VIII and factor IX preparations
c) SCREENING of Donors on the basis of history
• MOTHER TO INFANT TRANSMISSION:
– In Utero by TRANSPLACENTAL Spread
– During delivery through an INFECTED Birth Canal
– After birth by INGESTION of Breast Milk
– Antiretroviral therapy virtually ELIMINATES risk
Health Care Workers and HIV Risk
- Seroconversion has been documented after Accidental Needle-Stick Injury or exposure of nonintact skin to infected blood in laboratory accidents
- Risk after Needle-Stick accidents ~0.3% – Risk of HBV after needle-stick is ~30%
- Antiretroviral therapy given within 24 to 48 hours of a needle stick can REDUCE the Risk of INFECTION Eightfold
Epidemiology for HIV- Groups at High Risk
• Men who have sex with men
– Largest group (>50% of the reported cases) – On the DECLINE
• Heterosexual contacts (~20%)
– Globally the most common mode of transmission
• Intravenous Drug Abusers (~20%)
• Hemophiliacs (~0.5%)
– Received factor concentrates before 1985
- Recipients of Blood and Blood Components (~1%)
- HIV Infection of the newborn (~2%)
- ~5% NO Risk factors
Properties of HIV
• Two forms (similar):
– HIV-1: Most Common in the US, Europe, and Central Africa
– HIV-2: principally in West Africa and India
• Virus CORE Contais:
A) MAJOR CAPSID PROTEIN p24!!!!!!
i) Most abundant Viral Antigen
ii) ELIZA test used to diagnose HIV infection!!!!!!!!!!
B) Two copies of VIRAL GENOMIC RNA
C) Three Viral ENZYMES (Protease, Reverse Transcriptase, and Integrase)
• Core is surrounded by a Matrix Protein called p17!!!1
• Studding the Viral Envelope (critical for HIV infection of cells)
Integrase)
– Gp120 (Binding to CD4 and conformation change for CCR5) and Gp41 (FUSION with Cell)!!!!!!!!!!!!
HIV Infection
• HIV FIRST infects T cells, Dendritic cells, and Macrophages (all have CD4)!!!!!!!!!!
– Establishes itself in LYMPHOID TISSUES
- It can remain LATENT for long periods
- ACTIVE Viral Replication → more infection of cells → progression to AIDS
Chemokine Receptors
• HIV isolates can be distinguished by the receptor it uses:
1) R5 Strains use CCR5!!!!!!!!!!!!!
a) Preferentially infects cells of the Monocyte/Macrophage lineage (M-
TROPIC)!!!!!!!!!!!
b) 90% of cases, this strain DOMINATES in Acutely Infected
c) ~1% of white Americans (rarely Africans or East Asians) are HOMOZYGOUS for DEFECTIVE Copies of the CCR5 gene
– RESISTANT to INFECTION and the development of AIDS associated with R5 HIV isolates!!!!!!!!!!!!
d) ~20% of Individuals are Heterozygous
– Onset of disease after infection is delayed
2) X4 strains use CXCR4!!!!!!!
a) Preferentially infect T cells (T-TROPIC)!!!!!!!!!!!!!!
– Even infect thymic T-cell precursors → greater T-cell depletion and impairment
b) This strain GRADUALLY ACCUMULATIONS OVER TIME
3) R5X4 that DUAL-TROPIC!!!!!!!
HIV Infection Cont 1
• Infects memory and activated T cells
• Hard time infecting naive T cells
a) Contain an active form of an enzyme → MUTATIONS
in the HIV GENOME
*** APOBEC3G (for Apolipoprotein B mRNA-editing, Enzyme-catalytic, Polypeptide-like 3G)!!!!!!
b) HIV has evolved to counteract this:
• Viral protein VIF binds to APOBEC3G → DEGRADATION by cellular Proteases!!!!!!!!!!!
HIV Infection Cont 2
• THRIVES when the host T cells and Macrophages are ACTIVATED by antigenic stimulation
– By HIV itself
– By other infecting microorganisms
• Stimulation of Cells:
– Ultimately leads to release of NF-κB → goes to the Nucleus → INCREASED HIV DNA Transcription!!!!!!!!
T- Cell Depletion
• Mainly by DIRECT Cytopathic effects of the replicating virus
– ~100 billion new viral particles are produced every day → 1-2 billion CD4+ T cells die each day
– For a While, the immune system can REPLACE the dying T cells
i) But eventually, it CANT KEEP UP!!!!!
• Other mechanisms also contribute to T cell death
Macrophages in HIV
• HIV-1 can INFECT and MULTIPLY in TERMINALLY DIFFERENTIATED NON-DIVIDING Macrophages
– Dependent on the viral VPR gene!!!!!!!!!
• Quite Resistant to the Cytopathic effects of HIV
– May be RESERVOIRS of Infection
• May act as PORTALS of Infection
– 90% of Acute HIV infection is predominantly M- TROPIC Strains!!!!!!!!
Dendritic Cells in HIV
• MUCOSAL DENDRITIC CELLS:
– Infected and Transport it to regional LYMPH NODES:
a) Then TRANSMITTED to CD4+ T cells
b) LECTIN-LIKE RECEPTOR that specifically Binds HIV and DISPLAYS it in an Intact, infectious form to T cells!!!!!!
• FOLLICULAR DENDRITIC CELLS (in the LN’s):
– Potential RESERVOIRS of HIV
– Most Virus Particles are found on the SURFACE of their Dendritic Processes
– Trap HIV Virions coated with Anti-HIV antibodies
i) RETAIN the ABILITY to INFECT CD4+
B Cells and HIV
• POLYCLONAL ACTIVATION of B cells: – Germinal center B-cell HYPERPLASIA – Bone Marrow PLASMACYTOSIS – HYPERGAMMAGLOBULINEMIA – Formation of circulating immune complexes
• Patients with AIDS CANT MOUNT Antibody RESPONSES to Newly encountered Antigens
– Not just because of loss of T cell help!!!!!!!!
HIV and Brain
• Nervous system is a major target of HIV infection!!!!!!!!!!!!
– 40-60% have clinically apparent Neurologic Dysfunction
- Infects MACROPHAGES and MICROGLIAL cells
- Mechanism of HIV-induced damage of the brain is Poorly understood
Acute Retroviral Syndrome
- Clinical Presentation of the INITIAL Spread of the Virus and the Host response
- Seen in 40-90% of individuals who acquire the virus
- Typically occurs 3-6 WEEKS AFTER infection!!!!
- Resolves Spontaneously AFTER 2 - 4 WEEKS!!!!
• Symptoms:
– Sore Throat, Myalgias, Fever, Weight Loss, and Fatigue
– Rash, Cervical Adenopathy, Diarrhea, and Vomiting
Viral Load
• Extent of viremia (measures HIV-1 RNA levels in the blood)
• After INITIAL Viremia, infected persons reach a STEADY STATE for years
– Viral LOAD at this point can PREDICT RATE OF PROGRESSION
Clinical Latency Period
• Lymph Nodes and the Spleen are sites of continuous HIV replication and cell destruction
– Number of circulating blood CD4+ T cells steadily DECLINES!!!!!
• FEW or NO Clinical Manifestations
– Oral Candidiasis (thrush), Vaginal Candidiasis, Herpes Zoster, and maybe Mycobacterial Tuberculosis
– Autoimmune THROMBOCYTOPENIA
HIV Evades Immune Detection
- Destroys the CD4+ T Cells that are CRITICAL for Effective Immunity
- Antigenic VARIATION
• DOWN-MODULATION of Class I MHC molecules on infected cells!!!!!!!!!!
– Viral antigens are NOT Recognized by CD8+ CTLs
• May also Evolve and SWITCH FROM relying solely on CCR5 to enter its target cells to relying on either CXCR4 or BOTH CCR5 and CXCR4!!!!!!!!!!
– Associated with MORE RAPID DECLINE in CD4+ T-cell counts
Progression to AIDS
- Typically about 7-10 years
- Rapid progressors: 2-3 years
• Long-term Non-Progressors (5-15%)
– Asymptomatic, Stable CD4+ T Cell Counts, and LOW Viremia for 10 or more years
• ELITE CONTROLLERS (~1%)
– Undetectable Plasma Virus (less than 50 - 75 RNA Copies)
Clinical Features of AIDS
- Fever and Weight Loss
- Diarrhea
- Generalized LYMPHADENOPATHY
- Neurologic disease
- Multiple OPPORTUNISTIC INFECTIONS
- Secondary Neoplasms
Neoplasms
1) Karposi Sarcoma: HHV8
2) Primary Lymphoma of Brain: EBV
3) Invasive Cancer of Uterine Cervix: HPV (Also Anal Cancer)
Highly Active Antiretroviral Therapy (HAART)
• COMBINATION of 3-4 drugs that BLOCK Different Steps of the HIV life cycle!!!!!
• Dramatically ALTERS the Course of HIV infection and incidence of Opportunistic infections and tumors
– E.g. P. jiroveci and Kaposi sarcoma
• Can SUPPRESS Virus Levels BELOW the Level of Detection
– STOPS the LOSS of CD4+ T
– Over time, Peripheral CD4+ T-cell count SLOWLY INCREASE (often to normal)
• REDUCED TRANSMISSION of the virus
– Especially from infected mothers to newborns
• Concern that with more people living with HIV increased Risk of Spreading the infection IF Vigilance is relaxed
Downside of HAART
• IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME:
– Some patients with advanced Disease
– Antiretroviral therapy triggers a paradoxical clinical deterioration
– Occurs despite INCREASING CD4+ T Cell counts and DECREASING Viral Load
– Not understood why this Occurs
• ADVERSE SIDE-EFFECTS OF THE DRUGS:
– Lipoatrophy (loss of facial fat)
– Lipoaccumulation (excess fat deposition Centrally)
– Elevated lipids
– Insulin Resistance
– Peripheral Neuropathy
– Premature Cardiovascular Kidney and Liver Disease
Amyloidosis
• Extracellular deposits of FIBRILLAR PROTEINS → tissue damage and functional compromise
– Abnormal Fibrils are produced by the AGGREGATION of Misfolded proteins
– Fibrillar deposits bind a wide variety of Proteoglycans and Glycosaminoglycans
- Associated with a Number of INHERITED and Inflammatory Disorders
- Diagnosis usually made with TISSUE BIOPSY!!!!!!
Classifications of Amyloidosis
Hemodialysis- Associated Amyloidosis:
- Beta 2 Microglobulin!!!
Familial Mediterranean Fever:
- SAA!!!!
Organs Involved in Amyloidosis
• Amyloidosis Secondary to CHRONIC Inflammatory Disorders:
– Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid
– Other tissues as well
• Amyloidosis associated with PLASMA CELL PROLIFERATIONS:
– More often involves the Heart, Gastrointestinal Tract,
Respiratory Tract, Peripheral Nerves, Skin, and Tongue
– But not specific
• Localization of Amyloid DEPOSITS in Hereditary Syndromes is varied
Congo Red Stain for Amyloid
Classic Examples is the Liver (Apple- Green Bifuringence)
***Progressive Accumulation of Amyloid —-> Encroachment and Pressure Atrophy of Adjacent Cells
Clinical Features of Amyloidosis
- Incidental finding with no clinical manifestations
- Cause serious clinical problems and even death
- Symptoms DEPEND on the Magnitude of the Deposits and on the sites or organs affected
• Initial clinical manifestations are Nonspecific
– Weakness, Weight Loss, Light-Headedness, or Syncope
• Prognosis for generalized Amyloidosis is Poor
