ImmunoPathology Notes Apr 27, 2025 PDF

Goals 1. To learn the four classifications of hypersensitivity responses and examples of each 1. To learn the relationship between hypersensitivity responses and autoimmune diseases 1. To learn how loss of self-tolerance results in autoimmune disease 1. To learn primary and secondary immunodeficienc...

Goals 1. To learn the four classifications of hypersensitivity responses and examples of each 1. To learn the relationship between hypersensitivity responses and autoimmune diseases 1. To learn how loss of self-tolerance results in autoimmune disease 1. To learn primary and secondary immunodeficiency diseases and examples of each 1. To learn examples of autoimmune diseases 1. To learn the difference between primary and secondary immunodeficiency diseases Immunopathology ► Applying the concepts learned in the Immunology section to reactions and diseases we see in patients Immunopathology ► Part 1 - Hypersensitivity ► Part 2 - Autoimmunity ► Part 3 - Immunodeficiency ► Primary ► Secondary The main objective of the immune response: neutralize and remove the antigen/pathogen In infections, both the pathogen and the response to it cause tissue damage In hypersensitivity, the antigens are not destructive, but the responses to them cause tissue damage Outcome: anything from a small nuisance to death 1) The first step generates the effector cells and molecules that then produce… 2) The second step is responsible for the tissue damage Classification of Hypersensitivity reactions ► Classified based on the mechanisms of tissue damage ► Type I, Type II, Type III, Type IV ► Individual disorder may involve one or multiple mechanisms ► Both exogenous and endogenous antigens may elicit hypersensitivity reactions Type I Hypersensitivity Reactions: ► The players: ► Ig E mediated TH2 cells ► Ig E antibodies ► mast cells ► Requires repeat exposure to the allergen ► Initial Ig E production is favored by low antigen (allergen) dose ► Generally, high initial antigen dose induces tolerance ► Incidence is increasing in developed countries reason why is not clear Mast Cell Mediators ► ► ► Vasodilation, increased vascular permeability ► Histamine ► Neutral proteases that activate complement and kinins ► platelet-activating factor (PAF) ► Prostaglandin D2 ► Leukotrienes B4, C4, D4 Smooth muscle spasm ► Leukotrienes B4, C4, D4 ► Histamine ► Prostaglandins ► PAF Cellular infiltration ► Cytokines (e.g., chemokines, TNF) ► Leukotriene B4 ► Eosinophil and neutrophil chemotactic factors (not defined biochemically) Mast Cell Activation ► Immediate allergic reaction ► evident by 30 min, lasts ~ 1hour ► Late phase response ► recruited eosinophils, basophils, TH2 cells ► develops in 2 - 24 hours Type 1 Hypersensitivity Reactions ► Localized ► ► ► ► ► Allergic rhinitis Asthma Gastroenteritis: diarrhea, cramps Skin: Urticaria (hives) Systemic ► ► Usually follows injection (or ingestion) of an antigen in a susceptible individual Anaphylaxis Anaphylaxis ► Manifestations ► Widespread vascular dilation and leakage with drop in blood pressure ► Edema ► Bronchial constriction ► Runny nose, sneezing, coughing, swelling itching, vomiting, abdominal cramps, diarrhea, fainting ► Patient history may not contain helpful information ► First episode can be life threatening Type I Hypersensitivity: Predisposition ► Atopy ► a predisposition to develop localized immediate hypersensitivity reactions to inhaled and ingested antigens ► Atopic individuals tend to have: ► High serum Ig E ► More IL- 4 producing TH2 cells ► 50% of patients have a family history of allergies ► Genetic studies ongoing Alpha gal syndrome ► Unconventional food allergy ► IgE-mediated hypersensitivity responses to the glycan galactose-alpha-1,3-galactose (alpha-gal) - not to a foodprotein ► Lone star and Cayenne ticks in North America Symptoms ► Symptoms develop hours later, not in minutes like typical IgE mediated reaction ► Mostly skin reactions ► Itching, erythema, urticaria and angioedema ► Can also include abdominal pain and even anaphylaxis ► Rarely can see mouth itching and swelling Example Case ► 22 month old healthy baby boy ► At age 22 months developed swollen lips while eating a cookie with peanut butter ► 1 month later: while eating the same type of cookie, started to vomit, developed a horse voice, started to wheeze and developed facial swelling ► On the way to the emergency room, he became lethargic and lost consciousness. ► Low blood pressure, rapid pulse, rapid breathing ► At the emergency room he was given epinephrine, saline, Benadryl, and a corticosteroid Within minutes, hoarseness, BP, pulse and breathing improved 30 minutes later, all changed for the worse Treatment repeated, and additional airway measures were taken Repeated treatment in another 30 minutes 1 hr later – significant improvement, but face still swollen Admitted for observation; continued treatment w/Benadryl (diphenhydramine) and corticosteroid, facial swelling and wheezing subsided after 24 hrs; other signs normalized What are the players in Anaphylaxis ► Ig E antibody ► Mast cells ► Ig E antibody bound to mast cells at FcεRI receptor ► Inflammatory mediators released by mast cells Inflammatory Mediators Released by Mast Cells ►Histamine ► Increases vascular permeability ► Causes smooth muscle contraction ►Heparin ► Increases vascular permeability ► Causes smooth muscle contraction ►TNFα ► Causes activated macrophages to secrete nitrous oxides (NO) and reactive oxygen species (ROS) that can destroy tissue Type II Hypersensitivity Reaction: Antibody mediated ►Cell surface ‐ bound IgG ►IgG and IgM antibodies participate directly in injury to cells by promoting phagocytosis or lysis and injury to tissues by inducing inflammation ►Antibodies may interfere with cellular functions and cause disease without tissue injury ► Examples include: side effect of some drugs (including penicillin); transfusion reactions; mechanism of several autoimmune diseases Type II Hypersensitivity Examples Transfusion reactions Hemolytic disease of the newborn (erythroblastosis fetalis) Acute rheumatic fever streptococcal cell wall antigen; antibody cross reacts with a normal myocardial antigen Pernicious anemia (target antigen is intrinsic factor in stomach) Autoimmune hemolytic anemia, thrombocytopenia, agranulocytosis Some drug reactions (drug acts as a hapten attaching to the surface of RBCs) Type III Hypersensitivity Reaction ►IgG and IgM antibodies bind antigens usually in the circulation and the antigen-antibody complexes deposit in tissues and induce inflammation ►Neutrophils and monocytes that are recruited produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals Kumar. Robbins and Cotran Pathologic Basis of Disease, 9th Ed Fibrinoid Necrosis (Kumar 6-18) Type III Hypersensitivity Reaction Local response is called arthus reaction Cutaneous vasculitis Systemic response is called serum sickness Sometimes chronic supply of antigen (viral hepatitis, bacterial endocarditis) Get fevers, rash, arthritis, nephritis Reaction to penicillin is the most common cause of serum sickness in the US History: Use of horse serum from immunized horses for immunization against diptheria Type IV Hypersensitivity Reaction Type IV Hypersensitivity ► Cell mediated response ► CD4+ TH1 cells (and sometimes CD8+ T cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury ► CD4+ TH17 cells contribute to inflammation by recruiting neutrophils ►In some diseases, CD8 cytotoxic T lymphocytes (CTLs) directly kill tissue cells Type IV Hypersensitivity Reaction ►Cell ► ► - mediated (T cell mediated) Delayed type hypersensitivity ► PPD skin test for TB (mycobacterial molecules) ► Insect venom Swelling, erythema; cytokines made by Th1 cells activate macrophages ►Contact hypersensitivity ► Haptens (small molecules) like Nickel Pentadecacatechol (poison ivy) ► Contact dermatitis and mucositis Delayed type hypersensitivity Tuberculin (PPD) 48 hrs Case Presentation A 7 year old boy presented with itchy, red skin lesions on his hands and arms 2 days after a hike with his summer camp group Within 1 - 2 days he developed similar lesions on trunk, face, genitals Blisters with clear fluid developed There was slight relief with Benadryl There were no other signs/symptoms Contact sensitivity to poison ivy Type IV – Delayed hypersensitivity Antigen: pentadecacatechol Treatment was started with topical steroids, Benadryl, and washing with soap and water Lack of response, switched to systemic steroids Summary of Hypersensitivity Reaction ► Hypersensitivity reactions are classified on the basis of the mechanisms of tissue damage ► Type I, Type II, Type III, Type IV ► Individual disorder may involve one or multiple mechanisms ► Both exogenous and endogenous antigens may elicit hypersensitivity reactions Type Immune Mechanisms Histopathologic Lesions Prototypical Disorders Immediate (type I) hypersensitivity Production of IgE antibody → immediate release of vasoactive amines and other mediators from mast cells; later recruitment of inflammatory cells Vascular dilation, edema, Anaphylaxis; allergies; smooth muscle contraction, bronchial asthma (atopic mucus production, tissue forms) injury, inflammation Antibody-mediated (type II) Production of IgG, IgM → hypersensitivity binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes Immune complex– Deposition of antigenmediated (type III) antibody complexes → hypersensitivity complement activation → recruitment of leukocytes by complement products and Fc receptors → release of enzymes and other toxic molecules Phagocytosis and lysis of Autoimmune hemolytic cells; inflammation; in anemia; Goodpasture some diseases, functional syndrome derangements without cell or tissue injury Inflammation, necrotizing vasculitis (fibrinoid necrosis) Systemic lupus erythematosus; some forms of glomerulonephritis; serum sickness; Arthus reaction Cell-mediated (type IV) hypersensitivity Perivascular cellular infiltrates; edema; granuloma formation; cell destruction Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis Table 6-1 9th Ed Activated T lymphocytes → (1) release of cytokines, inflammation and macrophage activation; (2) T cell–mediated cytotoxicity Mechanisms of Hypersensitivity Reactions Kumar. Robbins and Cotran Pathologic Basis of Disease, Immunopathology Part 2 Autoimmune Diseases ►Autoimmune diseases occur when some aspect of self-‐tolerance is lost and an adaptive immune response is directed toward normal components of the healthy human body. Autoimmune Disease Chronic diseases caused by immune responses directed toward autologous (self) components of the body A defining characteristic of autoimmune diseases is the presence of antibodies and T cells specific for antigens expressed by the targeted tissue Autoantibodies and autoimmune T cells Autoantigens: Antigens expressed by the targeted tissue in autoimmune diseases Types of Immune Diseases Correspond to Types of Hypersensitivity Reactions ► Reactions ► Type II: Autoantibodies are directed against components of cell surfaces or the extracellular matrix ► Type III: Soluble immune complexes are deposited in tissues ► Type IV: Effector T cells Types of Autoimmune Diseases ► Systemic ► Organ/Tissue Specific Type III: Systemic Lupus Erythematosus (SLE) Cause: Unknown Female : Male ration 9 or 10:1 Age 15-50 years Circulating IgG antibodies specific for constituents of cell surfaces, cytoplasm and nucleus The binding of autoantibodies against cell - surface components initiates inflammatory reactions that cause cell and tissue destruction Sometimes, antibodies to erythrocytes cause autoimmune hemolytic anemia Antibodies to other blood cells 16 year old female Previously in good health Butterfly rash on face following sun exposure Stiff fingers and hips in morning Blood ANA titer 1:1280 Normal is less than 1:160 Anti-‐DNA Antibody + Low complement C3 Deposits of immune complexes in the skin Similar to Type III hypersensitivity reaction Lupus Erythematosus ►Mechanism Anti - nuclear antibody production is T cell dependent Broken T cell tolerance to self - antigens Antigen - antibody complexes deposit in kidneys and joints (small vessels), fix complement and tend to deplete C3 (low on blood tests) Photosensitivity not well understood, has to do with ultraviolet effects on cells in skin Management requires corticosteroids to suppress immune responses Rheumatoid Arthritis 1 - 3 % of US population Women/Men: 3/1 Chronic, episodic inflammation of joints Rheumatoid Factor (RF) – 80% of patients with rheumatoid arthritis have RF – Anti - immunoglobulin autoantibodies: IgM, IgG, and IgA antibodies specific for the Fc region of human IgG Chronic inflammation of synovium: Activated T cells, macrophages and plasma cells leads to- Progressive destruction of cartilage and bone Symmetric involvement of multiple joints TMJ involved in 50 - 60% Often occurs with other autoimmune diseases (e.g. Sjögren syndrome, Systemic Lupus Erythematosus, etc….) Rheumatoid Arthritis ► White blood cells infiltrate the joint synovium: ► CD4 and CD8 T cells, B cells, lymphoblasts, plasma cells, neutrophils, and macrophages ► plasma cells making rheumatoid factor ► Autoimmune CD4 T cells are activated by dendritic cells and these activate macrophages (which accumulate in the inflamed synovium) ► Prostaglandins and leukotrienes produced by inflammatory cells mediate inflammation Rheumatoid Arthritis The damage done Pro - inflammatory cytokines recruit further effector cells into the joints increases tissue erosion Proteinases and collagenases produced by inflammatory cells within the joint damages cartilage and supporting structures such as ligaments, tendons, and eventually the bones Neutrophils release lysosomal enzymes into the synovial space causing damage to the tissue and proliferation of the synovium Autoimmune Diseases Endocrine glands often involved ►Synthesis and secretion of a particular hormone ►Involves tissue - specific proteins not expressed in other cells or tissues ►They secrete their hormones into the blood ►Endocrine tissue is well vascularized facilitates interactions with cells and molecules of the immune system Autoimmune Disease Endocrine Glands - Results ► Each autoimmune disease is due to impairment of a single type of epithelial cell within the endocrine gland ► Loss of endocrine function has drastic systemic effects including pronounced morbidity and sometimes death Thyroid The thyroid gland regulates the basal metabolic rate of the body By secreting tri-iodothyronine (T3) and tetra iodothyronine (thyroxine or T4) The epithelial cells of the thyroid make a large glycoprotein called thyroglobulin stored within follicles Thyroid cells are uniquely specialized to take up iodine used to iodinate and crosslink the tyrosine residues of stored thyroglobulin Thyroid ► When increased cellular metabolism is required (ex. when the outside temperature drops) ► nervous system triggers the pituitary to secrete thyroid-stimulating hormone (TSH) ► Surface receptors on thyroid cells bind TSH which inducing the endocytosis of iodinated thyroglobulin ► release of thyroid hormones by proteolytic degradation of the protein ► As blood levels of thyroid hormones rise they feed back on the pituitary, inhibiting the further release of TSH Graves’ Disease Hyperthyroidism (increased T3 and T4 levels in serum) Symptoms are caused by autoantibodies that bind to the TSH receptor CD4 TH2 response Heat intolerance, nervousness, irritability, warm moist skin, weight loss Thyroid enlargement Bulging eyes (proptosis) and characteristic stare binding of autoantibodies that react with muscles of the eye Treatment: Drugs that inhibit thyroid function, removal of the thyroid, radioisotope destruction of the thyroid Hashimoto Disease (Chronic Thyroiditis) ► Thyroid loses the ability to make hormones ► T3 and T4 ► CD4 TH1 response: Both antibodies and effector T cells specific for thyroid antigens are produced ► Lymphocytes infiltrate the thyroid resulting in a progressive destruction of normal thyroid tissue ► Patients become hypothyroid and eventually unable to make thyroid hormone ► Treatment: Replacement therapy Pancrease - Type 1 Diabetes Mellitus ► Selective autoimmune destruction of the Islets of Langerhans ► insulin - producing cells of the pancreas ► Pancreas contains about half a million islets, each consisting of a few hundred cells, each programmed to make a single hormone: ► α cells make glucagon ► β cells make insulin ► δ cells make somatostatin From Quizlet.com Type 1 Diabetes Mellitus ► Antibody and T-cell responses against insulin, glutamic acid and decarboxylase, and other specialized proteins of the pancreatic β cell ► CD8 T cells specific for peptide antigens unique to β cells mediate β – c e l l destruction, gradually decreasing the number of insulin - secreting cells ► Individual islets become successively infiltrated with lymphocytes ► Disease begins when there are insufficient β cells to provide the insulin necessary to control the level of blood glucose HLA: The Dominant Genetic Factor Affecting Susceptibility to Autoimmune Disease while different HLA alleles may contribute to a disease, their presence is not, by itself, the cause of any disease Autoimmune Diseases: Infections as Triggers ► During infections, antigen presenting cells may present self-antigens AND express co-stimulatory receptors to activate T cells (no anergy) ► Previously hidden self - antigens can be released during responses to infections and stimulate B cells ► Microbial antigens may mimic self-‐antigens (molecular mimicry) ► Also has HLA association Rheumatic Fever ► Initial infection with stretptococcus pyogenes ► Antibodies specific for cell - wall components of S. pyogenes are made ► Some of these antibodies happen to react with epitopes present on human heart, joint and kidney tissue ► On binding to the heart, they activate complement and generate an acute and widespread inflammation - rheumatic fever ► May cause permanent tissue damage/heart failure Rheumatic fever is a transient autoimmune disease - Without T - cell help the autoantigens cannot continue to stimulate antibody synthesis - This situation arises because the CD4 T - cells that helped in the antibacterial response are not stimulated by the autoantigens The incidence of rheumatic fever has greatly diminished since streptococcal infections began to be treated with antibiotics Hypothesis: Increased Incidence of Hypersensitivity and Autoimmune Diseases ► Modern practices of hygiene, vaccination, and antibiotic therapy cause some children’s immune systems to develop in ways that are different from those achieved in former times ► Because children’s immune systems are not tried out against such a range or variety of childhood infections, they do not become so skilled in attacking infection while maintaining tight T - cell tolerance Immunopathology Part 3 Immunodeficiency Types of Immunodeficiencies Primary: – – – – – Most are inherited Most are congenital Often significant family history Can present initially in children and adults Some are combined with other congenital defects Secondary: – Induced by environmental, infectious or iatrogenic factors – Examples: malnutrition, HIV infection, radiation, chemotherapy, cancer, other systemic illnesses Primary Immune Deficiencies ► X-‐Linked Agammaglobulinemia (Bruton's Agammaglobulinemia) ► Common variable immunodeficiency ► Isolated IgA Deficiency ► Hyper-‐IgM Syndrome ► DiGeorge Syndrome (Thymic Hypoplasia) ► Severe Combined Immunodeficiency ► Deficiencies in Phagocyosis Secondary Immune Deficiencies ► Malnutrition associated immune deficiency ► Radiation induced immune deficiency ► Acquired Immunodeficiency Syndrome (AIDS) ► Diabetes mellitus ► Medication reactions Primary Immunodeficiencies >150 primary immunodeficiencies identified Incidence unknown – Estimates vary in the literature; as a group, between 1:2000 and 1:10,000 of live births – The most common is IgA deficiency (1:500) Patients have an increased susceptibility to infections, autoimmune diseases and cancer One or more components of the immune system involved Relative prevalence of various primary immunodeficiencies Diseases affect innate immunity (phagocytes, NK cells, or complement) or the humoral and/or cellular arms of adaptive immunity (mediated by B and T lymphocytes) Predominantly antibody deficiencies ~ 65% Combined T and B cell deficiencies Phagocytic defects ~ 15% ~ 10% Other cellular immunodeficiencies ~5- 10% 89 Primary Immunodeficiencies: Diagnosis and Treatment Many types of diagnostic tests available Blood cell count with differential is number one used CBC with differential Immunoglobulin evaluations in most cases Special tests, as indicated Therapy and prophylaxis always requires anti - microbials Treatment: depends upon specific disorder; options include immunoglobulin replacement and hematopoietic stem cell transplantation 90 Primary Immune Deficiencies ► X - Linked Agammaglobulinemia (Bruton's Agammaglobulinemia) ► Hyper - IgM Syndrome ► Common variable immunodeficiency ► Isolated IgA Deficiency ► DiGeorge Syndrome (Thymic Hypoplasia) ► Severe Combined Immunodeficiency ► Deficiencies in Phagocyosis X - linked Agammaglobulinemia (Bruton’s Agammaglobulinemia) ►X-linked recessive ► Mutation of the BTK gene ► Almost entirely in males ► Disease presents at ~6 months of age (as maternal immunoglobulins are depleted) 91 X - linked Agammaglobulinemia ►B cell problem - B cell precursors stop maturing before completing immunoglobulin gene development ► Bacterial Infections (no opsinization) ► Haemophilus influenzae, Strep. pneumoniae, Staph. Aureus ► GI viral Infections: coxsackie virus, poliovirus, etc. ► Low to no B cell numbers in the blood ► ► Immature B cells in bone marrow normal ► All antibodies depressed (in most cases) Secondary lymphoid organs affected ► ►T ► Germinal centers are underdeveloped cells are normal Most intracellular viruses taken care of by normal T cells ►Treated with IV Ig 92 X - linked Hyper - IgM Syndrome ► Most cases have normal or elevated IgM ► Very low or no IgA, IgE and IgG ► Symptoms typically in first or second year of life ► Recurrent pus-producing (pyogenic) bacterial infections of the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs ► Because levels of opsonizing IgG are low ► Five different types (types 1-5) ► distinguished by the location of the gene mutation involved 96 X - linked Hyper - IgM Syndrome ► 70% X-‐linked ► Gene for CD40L is on the X chromosome ► 30% autosomal recessive ► Loss of function in CD40 or the enzyme needed for Ig class switching ► CD40L is needed to communicate with Ag - specific B cells, as well as with dendritic cells and macrophages ► B cells cannot switch to IgG, IgA or IgE and cannot expand in lymph nodes ► Macrophage interaction with T cells depends on CD40L on T Cell and CD40 receptor on macrophage 96 Common Variable Immunodeficiency ► Heterogeneous group of disorders, poorly defined ► all with hypogammaglobulinemia ► M&F ► Onset: Childhood (and later) ► Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) ► Increased risk of autoimmune disease and lymphoid malignancies Common Variable Immunodeficiency ► Deficiency in all antibody classes ► Subset of patients just IgG deficiency ► Clinical presentation is similar to X-linked agammaglobulinemia ► Normal numbers of circulating B cells ► not able to differentiate to plasma cells Isolated IgA Deficiency ► 1/500-600 individuals of European descent (much rarer in individuals of African or Asian descent) ► Familial and Acquired (Infections) forms ► Low levels of serum and secretory IgA ► Impaired differentiation of B lymphocytes to IgA producing plasma cells ► Molecular basis not yet known ► Results: Respiratory, GI and GU infections ► Respiratory allergy, SLE, RA DeGeorge Syndrome (Thymic Hypoplasia) ► T - cell deficiency ► Results from failure of development of the third and fourth pharyngeal pouches ► Variable loss of T cell - mediated immunity ► Hypoplasia or lack of the thymus ► Tetany: lack of the parathyroids ► Congenital defects of the heart and great vessels ► Appearance of the mouth, ears, and facies may be abnormal. ► DiGeorge syndrome is not an inherited/familial disorder ► Greater then 50% have a deletion of a gene that maps to chromosome 22q11 DeGeorge Syndrome (Thymic Hypoplasia) ► Low numbers of T lymphocytes in the blood and lymphoid tissues ► The T - cell zones of lymphoid organs are depleted ► paracortical areas of the lymph nodes and the peri-arteriolar sheaths of the spleen ► Ig levels may be normal or reduced, depending on the severity of the T‐cell deficiency ► Result: Fungal and viral infections Severe Combined Immunodeficiency(SCID) ► Constellation of genetically distinct syndromes, all having in common defects in both humoral and cell-mediated immune responses ► Genetic abnormalities (autosomal or X-‐linked): ► Deficiencies in signaling through cytokine receptors for IL-‐ 2, IL-‐7, IL-‐15; other signaling defects ► Result in various combinations of B, T and NK deficiencies ► Often, the SCID defect resides in the T - cell compartment, with a secondary impairment of humoral immunity Severe Combined Immunodeficiency(SCID) ► Affected infants present with oral candidiasis, extensive diaper rash, and failure to thrive ► Recurrent, severe infections by a wide range of pathogens, including Candida albicans, P. jiroveci, Pseudomonas, cytomegalovirus, varicella, and a whole host of bacteria ► Lymphopenia, agammaglobulinemia, lack of tonsils, lack of lymph nodes ► Treatment: Bone marrow transplant (up to 95% survival); gene transfer 10 2 Phagocyte Deficiencies Leukocyte Adhesion Deficiency ► Phagocytes lack functional integrins – unable to migrate ► Cannot phagocytose and destroy bacteria opsonized by complement ► Persistent bacterial infections ► In oral cavity see gingival/periodontal infection 10 yr-old with LAD Leukocyte Adhesion Deficiency (LAD) A. Majorana et al. OOOOE, 1999; 87:691 Hx of ear and perirectal infections, skin and mucosal infections, sepsis Leukocytosis Severe pre-pubertal periodontitis, oral 10 ulcers 4 Chronic Granulomatous Disease ► Phagocytes cannot produce superoxide radicals ► Chronic infections with formation of granulomas ► aggregates of epithelioid macrophages, lymphocytes and plasma cells 10 5 See granulomatous reactions with: Bacterial infections; fungal infections; foreign body (non-infectious); hypersensitivity reactions Granuloma 106 Clinical presentation Examples of common primary immunodeficiencies ► Broad infectious susceptibility and failure to thrive ► Severe combined immunodeficiency (SCID) ► Other combined immunodeficiencis ► Wiskott–Aldrich syndrome ► (Progressive depletion of T cells) ► DiGeorge syndrome 10 9 Clinical presentation Examples of common primary immunodeficiencies ► Recurrent sino-pulmonary infections ► Common variable immunodeficiency (CVID) ► X-linked agammaglobulinemia (XLA) ► Complement deficiencies: C3 deficiency (classical and alternative pathways) susceptibility to pyogenic infections ► IgA deficiency Clinical presentation Examples of common primary immunodeficiencies Fungal Infections Thymic Hypoplasia Viral Infections (DeGeorge Syndrome) Severe combined immune deficiency (SCID) 112 Primary immunodeficiencies ► Should be considered when infections are (any of the following): ► recurring or chronic ► result in organ damage ► respond poorly to standard antimicrobials ► caused by poorly virulent or opportunistic organisms ► recurrent and caused by the same pathogen ► Early diagnosis of primary immunodeficiencies results in improved clinical outcomes Examples of phagocyte deficiencies: Neutropenia (reduction in neutrophils) ► Reduction in white blood cell count < 1500/μl (Normal =1,500 to 8,000/mm3) ► Secondary to ► Drugs: Anti-cancer chemotherapeutic agents, antibiotics, other ► Infections: Viral hepatitis A and B, rubella, measles, varicella, HIV, typhoid, TB, etc. ► Destruction of bone marrow by malignancies, etc. 114 Neutropenia ► Bacterial infections ► Staph. Aureus ► gram- negative bacteria in middle ear, oral cavity, perirectal area ► Gingival ulcerations ► NOTE: primary and secondary neutropenia have similar clinical features 115 Examples of phagocyte deficiencies: Severe reduction in neutrophils: Agranulocytosis WBC