The case
Define the term Hapten. What molecule acts as a Hapten in our case?
Haptens are small molecules that requires a carrier, usually a protein, to elicit an immune response. Toxicodendron genus produces urushiol oils which then require a human carrier protein to be antigenic.
A 32-year-old pregnant woman (para 2) presents to the clinic for a routine ultrasound; Figure A displays the ultrasound findings. The fetus has become anemic and levels of unconjugated bilirubin have increased dramatically. Which type of hypersensitivity reaction has occurred and what is mediating the disease state?
FIGURES:
A
A Type I hypersensitivity; antibody-mediated opsonization
B Type II hypersensitivity; antibody-mediated opsonization
C Type II hypersensitivity; cell killing via cytotoxic T cells
D Type III hypersensitivity; cell killing via cytotoxic T cells
E Type IV hypersensitivity; cell killing via NK cells
The clinical presentation and ultrasound is consistent with hydrops fetalis (the most severe form of erythroblastosis fetalis), an example of a type II hypersensitivity reaction, in which antibodies bind to antigens on a cell's surface leading to phagocytosis or lysis. Note the presence of edema in the ultrasound image (Figure A).
In hydrops fetalis, an Rh- pregnant woman who has previously been exposed to the Rh antigen mounts an immune response when exposed to fetal Rh antigen. This response leads to the production of IgM and IgG. IgG crosses the placenta into fetal circulation, binding fetal RBCs, targeting them for destruction. This accounts for the fetal anemia and increased unconjugated bilirubin.
Incorrect Answers:
Answer 1: Anaphylaxis would be more consistent with a type I hypersensitivity reaction.
Answer 3: The main route of RBC lysis in fetal hydrops is via antibody-mediated opsonization, not cytotoxic T cells.
Answer 4: Type III hypersensitivity reactions involve the deposition of immune complexes, not antibody-mediated opsonization.
Answer 5: Type IV hypersensitivity reactions are delayed-type and are mediated by T-cells, not NK cells.
A 22-year-old woman presents to her primary care physician because she has been having severe pruritus on her left leg. She says the symptoms started 1 week ago after she went on a hiking trip with her friends. She wore shorts during the hike and felt as if something brushed her skin on the front of her leg just below the knee. She has no past medical history and no family history of autoimmune diseases. On physical exam, she has red pruritic papules and vesicles on her left leg. Which of the following mechanisms was most likely involved in the development of this patient's symptoms?
A Activation of cell surface receptors by antibodies
B Cross-linking of IgE antibodies
C Cytotoxicity due to antibodies
D Cytotoxicity due to T-cells
E Immune complex deposition
This patient with pruritic papules and vesicles most likely has poison ivy-triggered contact dermatitis, which is a type IV hypersensitivty reaction involving T-cell activation.
Contact dermatitis is an erythematous and pruritic rash caused by cutaneous exposure to allergens or irritants. For example, poison ivy releases urushiol, which can penetrate the skin and modify endogenous proteins in the body. These modified proteins then become allergenic and activate a T-cell mediated response. This is a delayed reaction so symptoms will not present until 12-48 hours after exposure to the allergen. Notably, since this reaction is mediated by activation of T-cells, contact dermatitis is classified as a type IV hypersensitivity reaction.
Incorrect Answers:
Answer 1: Activation of cell surface receptors by antibodies is consistent with type II hypersensitivity; however, contact dermatitis is a type IV hypersensitivity reaction.
Answer 2: Cross-linking of IgE antibodies is consistent with type I hypersensitivity; however, contact dermatitis is a type IV hypersensitivity reaction.
Answer 3: Cytotoxicity due to antibodies is consistent with type II hypersensitivity; however, contact dermatitis is a type IV hypersensitivity reaction.
Answer 5: Immune complex deposition is consistent with type III hypersensitivity; however, contact dermatitis is a type IV hypersensitivity reaction.
A 20-year-old man has noted a cluster of small lesions on his upper lip for the past 5 days. On physical examination, there are four lesions ranging from 0.2 to 0.5 cm that are raised and filled with clear fluid. Which of the following descriptive terms best applies to his lesions?
A Bullae
B Macules
C Papules
D Pustules
E Vesicles
E Vesicles have a maximum size of 5 mm. They are often easily traumatized and unroofed to leave shallow ulcer-ations. In this case, herpetic vesicles are most likely present. Bullae are also fluid filled, but larger than 0.5 cm. Macules are not raised. They are flat areas less than 0.5 cm and distinguished by a difference in color; if the area is larger than 0.5 cm, then it is a patch. Papules are elevated and less than 0.5 cm; if larger, the term nodule is applied; either may be dome-shaped or flat-topped. Pustules are raised and filled with leukocytes to impart a yellow color.
What is the overall function of the lymphatic system?
What results when there is an imbalance of fluid removed from local tissue?
Removes excess fluid from tissues, transports WBCs, fatty acids and fats as chyle, and proteins. It is the waste management system of the body.
Imbalance: lymphedema
A Langerhans cell in the stratum spinosum layer of the epidermis has come into contact with a foreign antigen. After migrating to a nearby regional lymph node the Langerhans cell presents antigen via MHC class II and TCR interaction, CD4 co-stimulation, as well as B7 from the LDC interacting with CD28 of the CD4 positive T cell. Which Interleukin is expressed by the LDC that induces Th1 maturation?
IL-12
A 4-year-old boy is brought by his mother to the emergency room after the child was bitten by a rattlesnake one hour prior to presentation. The child was reportedly playing in the backyard alone when his mother heard the child scream. She rushed out to her child and found a snake with a rattle on its tail slithering away from the child. On examination, the child has a bleeding bite mark and significant swelling over the dorsal aspect of his right hand. He is in visible distress and appears pale and diaphoretic. The child undergoes fluid resuscitation and is placed on supplemental oxygen. He is administered rattlesnake antivenom and is admitted for observation. He is subsequently discharged 24 hours later feeling better. However, 6 days after admission, he presents again to the emergency department with a temperature of 102°F (38.9°C), diffuse wheals, and knee and hip pain. This patient’s condition is caused by which of the following?
A Antibodies directed against cell membrane antigens
B Antibodies directed against cell surface receptors
C Antibody-antigen complex deposition
D Cell-mediated direct killing
E IgE-mediated mast cell degranulation
The patient in this vignette presents with fever, urticaria, and arthralgia following administration of exogenous protein (antivenom) suggestive of serum sickness. Serum sickness is a type III hypersensitivity reaction characterized by immune complex deposition in affected tissues.
Serum sickness is caused by IgG antibodies complexing with self or foreign antigens. The most common causes of serum sickness are antitoxins and equine- or murine-derived antisera for hematologic cancer therapy. These antibody-antigen complexes subsequently deposit in peripheral tissues leading to fever, urticaria, arthralgia, and proteinuria. This represents a type III hypersensitivity reaction. Other type III hypersensitivity reactions include systemic lupus erythematosus, polyarteritis nodosa, and post-streptococcal glomerulonephritis.
Incorrect Answers:
Answer 1: Type II hypersensitivity reactions refer to cytotoxic antibody-mediated activation of complement and inflammatory cells against self-antigens on the cell surface. Examples of type II hypersensitivity reactions include autoimmune hemolytic anemia and rheumatic heart disease.
Answer 2: Type V hypersensitivity is often considered to be a subset of type II hypersensitivity in which antibodies bind to cell surface receptors rather than cell surfaces directly. Examples of type V hypersensitivity reactions include Graves’ disease and myasthenia gravis.
Answer 4: Type IV hypersensitivity reactions refer to cell-mediated direct killing of target cells. Examples of type IV hypersensitivity reactions include type I diabetes and contact dermatitis.
Answer 5: Type I hypersensitivity reactions refer to IgE-mediated degranulation of pro-inflammatory mediators in response to re-exposure to an allergen. Examples of type I hypersensitivity reactions include anaphylaxis, asthma, and allergic rhinitis.
A mother brings her 4-year-old daughter to the pediatrician complaining of a skin rash. The rash has appeared intermittently since the child was born and has started to become more frequent since the child started pre-school. The mother is worried about permanent skin damage, especially since the child keeps itching the rash. She has applied multiple over-the-counter ointments without effect. She denies any recent history of travel, extended time outdoors, or being around pets. The child’s history is notable for allergic rhinitis. A notable physical examination finding at the flexural areas of the knees is shown in Figure A. This finding is also seen in flexural areas of the elbows. The most likely cause of this patient’s symptoms is an example of which of the following types of disorders? Review Topic
QID: 109089
FIGURES:
A
Type I hypersensitivity
Type II cytotoxic hypersensitivity
Type II non-cytotoxic hypersensitivity
Type III hypersensitivity
Type IV hypersensitivity
In a pediatric patient with a history of seasonal allergies and physical examination findings consistent with an erythematous rash in the flexural regions of the upper and lower extremities, atopic dermatitis is the most likely diagnosis which is caused by a type I hypersensitivity reaction.
Type I hypersensitivity is caused by antigen crosslinking of IgE on sensitized mast cells. This causes the release of vasoactive mediators (e.g., histamine, leukotrienes, prostaglandin D2) and inflammatory mediators (e.g., TNF-alpha, leukotriene B4). This same mechanism is responsible for asthma, allergic rhinitis (hay fever), anaphylaxis, angioedema, urticaria, and allergies to medications and food.
Figure A demonstrates the characteristic appearance of an atopic dermatitis rash. These rashes frequently present as erythematous plaques and papules around the flexor surfaces of the elbows and knees. Excoriations, scaling, and vesicles can sometimes be seen. Of note, infants often have lesions on the cheeks, scalp, and extensor surfaces while older children and adults have lesions on the flexor surfaces.
A 46-year-old woman comes to the emergency department because of fever, abdominal pain, and a rash for the past 6 hours. She had leukemia six months ago for which she received a bone marrow transplant. Physical examination shows diffuse erythematous macules and an enlarged liver. Which of the following cell types most likely initiates the initial inflammatory response responsible for this pathology?
Elimination tool
A) B cells
B) Dendritic cells
C) Mast cells
D) Neutrophils
E) T cells
Answer: E) T cells
Graft-versus-host disease is characterized by transplanted immunocompetent cells attacking host tissues, most typically in the skin, liver, and intestinal epithelium. Although many different cell types can be found at the site of the epithelial lesions, the inflammatory response is initiated by CD4+ and CD8+ T cells from the graft.
Draw the general structure of an antibody.
Got it?!
CD8 positive T cells are also involved in type IV hypersensitivity reactions. They recognize antigens present on MHC class I and release enzymes that destroy and afflicted/infected host cell. What are the two major enzymes involved in this process?
Perforins and Granzymes
A 30-year-old Caucasian male presents with hemoptysis and uremia. Blood tests show the presence of anti-basement membrane antibodies specific for collagen located in glomerular and pulmonary basement membranes. The patient undergoes plasmaphoresis to help reduce the amount of anti-basement membrane antibodies. Which of the following diseases is of the same hypersensitivity category as this disease?
A Myasthenia gravis
B Systemic lupus erythematosus
C A PPD test
D Seasonal allergies
E Poison ivy rash
A: The disease the above patient presents with is Goodpasture's syndrome (anti-glomerular basement membrane disease), a type II hypersensitivity reaction (antibodies are generated that bind to an aspect of collagen IV molecules located in the basement membrane of glomeruli and alveoli). Myasthenia gravis is also a type II hypersensitivity reaction
A 5-year-old African American female has experienced recurrent respiratory infections. To determine how well her cell-mediated immunity is performing, a Candida skin injection is administered. After 48 hours, there is no evidence of induration at the injection site. Of the following cell types, which one would have mediated the reaction?
A Plasma cells
B Basophils
C T-cells
D Mast cells
E Fibroblasts
C: As most people have been previously exposed to Candida, Candida skin injection is a good test for examining delayed-type hypersensitivity and T-cell-mediated cellular immunity.
Primary exposure to the antigen leads to the production of T-cells that will be sensitized to the presence of the antigen upon secondary exposure. Following repeat exposure, antigen presenting cells present the antigen to sensitized CD4+ T-cells (particularly TH1 cells). After presentation, these TH1 cells begin producing and secreting factors, such as IFN-gamma and IL-12, that lead to macrophage activation and an inflammatory response.
Wilson et al. describe the symptoms of DiGeorge Syndrome, which is a disease that leads to a deficiency of T-cells. DiGeorge Syndrome is a genetic abnormality caused by a deletion of chromosome 22. Because of this deletion, there is not proper formation of the thymus (among other organs and structures). As a result, there is decreased/absent T-cell-mediated immune responses.
What is the MOA, spectrum, excretion, and adverse reactions of Flouroquinolones? Is it Bactericidal or Bacteriostatic?
DNA gyrase inhibitors, gram negative spectrum, renal excretion, adverse reactions include tendon rupture, and neurotoxicity. It is Bactericidal.
Septic shock criteria?
SIRS Criteria:
A 23-year-old man comes to clinic with a three-day history of a pruritic rash in both antecubital fossae. He states that he just returned from a family hiking trip in Maine and that he has had no fevers or other symptoms. His vital signs are within normal limits. On exam, both antecubital fossae are notable for erythematous patches with linear excoriations and scale, as shown in Figure A. Which of the following is his condition most likely associated with?
A Nail Pitting
B White streaks in oral mucosa
C History of asthma
D Increased serum IgA
E Type IV hypersensitivity reaction
This patient’s exam is consistent with atopic dermatitis (eczema), which manifests as erythematous, pruritic papules with scales that especially involve flexural surfaces. Atopic dermatitis is associated with a history of atopy, including conditions like asthma and allergic rhinitis.
Atopic dermatitis is a chronic and relapsing disease that most often occurs in someone with a childhood history of atopy. Atopic dermatitis can first present in childhood when it tends to favor the extensor surfaces and the cheeks. In adults; however, the lesions generally favor the neck and flexural areas such as the antecubital and popliteal fossae. Atopic dermatitis is a type I hypersensitivity reaction and involves elevated serum levels of IgE. Light microscopy of a skin biopsy would demonstrate spongiosis, which is edema of the epidermis.
Figure A shows erythematous lesions with scale in antecubital fossa, which is consistent with the flexural surfaces that atopic dermatitis favors. Illustration A is a histopathological slide demonstrating spongiosis in the epidermis, as seen in dishidrotic eczema. Spongiosis refers to intercellular edema, as labeled by the green arrow.
Incorrect Answers:
Answer 1: Nail pitting can be seen in psoriasis, which can also present with an erythematous, pruritic rash. These rashes tend to clearly demarcated plaques with scale, and tend to be more on extensor surfaces rather than flexural surfaces.
Answer 2: Wickham’s striae are characteristic of lichen planus. This patient’s lesions are not consistent with lichen planus, which can be remembered by the 5 P’s: Purple (violaceous), Planar, Polygonal, Pruritic Papules.
Answer 4: Atopic dermatitis is associated with increased serum IgE levels not IgA. Elevated levels of IgA can be seen in Wiskott-Aldrich syndrome, which also presents with thrombocytopenia and recurrent infections.
Answer 5: Allergic contact dermatitis, such as from environmental urushiol, is a type IV hypersensitivity reaction. These rashes tend to be severely pruritic and can have vesicles.
A 25-year-old woman with no prior medical history presents with complaints of a new skin rash. She was in her usual state of health until one month ago when she began developing an itchy rash on her lower abdomen. The patient works as a fitness instructor. Her family history is notable for a father with psoriasis and a brother with atopic dermatitis. Physical exam is notable for an otherwise healthy-appearing female and Figure A on skin exam. Her temperature is 98.9°F (37.2° C), pulse is 80/min, blood pressure is 120/82 mmHg, respirations are 10/min, and O2 saturation is 99% on room air. Her laboratory results are as follows: Serum: Na+: 135 mEq/L K+: 4.2 mEq/L HCO3-: 25 mEq/L Cl-: 100 mEq/L BUN: 19 mg/dL Creatinine: 1.0 mg/dL
Glucose: 94 mg/dL Hemoglobin: 14.4 g/dL Leukocyte count: 10,000 cells/mm^3 Platelet count: 380,000/mm^3 Which of the following is the mechanism underlying this patient’s skin findings?
A. IgE-mediated hypersensitivity
B. Immune complex-mediated hypersensitivity
C. T-cell-mediated hypersensitivity
D. Fungal infection
E. Deficiency of filaggrin
Marlen?
A 32-year-old female presents with a three month history of oral ulcerations and blisters throughout her body. When the physician examined the skin, she noted that when the skin was rubbed it sloughed off and formed blisters within a few minutes. A skin biopsy was performed and analyzed via immunofluorescence using anti-IgG antibodies (Figure A). Which of the following antibodies is also involved or found in a similar type of hypersensitivity reaction as in the case mentioned?
FIGURES:
A
A IgE against the proteins in apitoxin
B Anti-glomerular basement membrane
C Anti-dsDNA
D IgE against pollen
E Anti-Smith
B: The female in the clinical vignette has pemphigus vulgaris which is a type II hypersensitivity reaction caused by antibodies against desmosomes, specifically the protein desmoglein 3. Anti-glomerular basement membrane antibodies cause Goodpasture's syndrome which is a type II hypersensitivity reaction.
After receiving a blood transfusion contaminated with hepatitis B virus via the left median cubital vein (the one typically used for blood donations), at what site will evidence of lymphocyte activation against the pathogen most likely be observed first?
Spleen, it is a reservoir for lymph tissue.
What are the contents of the carotid sheath?
Common carotid, internal jugular, and vagus nerve.
A patient who has previously been sensitized to Urushiol from poison ivy plants again comes into contact with the plant while working in the yard. Draw on the board the immunopathology that would occur. Include the terms APC, Th1/Th17, IFN-gamma, and macrophage. Include the cytokines released by macrophages that cause tissue damage and clinical presentation.
Got it?!
Cytokines released --> IL-1, IL-6, TNF-alpha
A 9-year-old boy is brought to the emergency department by his parents with a 2-day history of weakness and joint pain. He was adopted 3 weeks ago from an international adoption agency and this is his first week in the United States. He says that he has been healthy and that he had an episode of sore throat shortly before his adoption. Physical exam reveals an ill-appearing boy with a fever, widespread flat red rash, and multiple subcutaneous nodules. The type of hypersensitivity seen in this patient's disease is also characteristic of which of the following diseases?
A Asthma
B Contact dermatitis
C Goodpasture syndrome
D Osteogenesis imperfecta
E Serum sickness
This patient with fever, red rash, joint pain, and subcutaneous nodules several weeks after a sore throat most likely has rheumatic fever, which is a type 2 hypersensitivity reaction like Goodpasture syndrome.
Type 2 hypersensitivity reactions are caused by antibodies that are directed against tissue-specific antigens. Binding of these autoantibodies to the endogenous targets can result in opsonization, complement activation, neutrophil and macrophage recruitment, or inhibition of a receptor. Together, these activities disrupt the function of the tissue and lead to pathology. One example of a type 2 hypersensitivity reaction is rheumatic fever, which is triggered by molecular mimicry between the Streptococcus pyogenes M protein and endogenous proteins. The antibodies formed in this disease bind to diverse tissues and cause the classic symptoms of rheumatic fever.
Incorrect Answers:
Answer 1: Asthma is an example of a type 1 hypersensitivity reaction rather than a type 2 hypersensitivity reaction.
Answer 2: Contact dermatitis is an example of a type 4 hypersensitivity reaction rather than a type 2 hypersensitivity reaction.
Answer 4: Osteogenesis imperfecta is not caused by a hypersensitivity reaction but rather by a genetic deficiency of collagen.
Answer 5: Serum sickness is an example of a type 3 hypersensitivity reaction rather than a type 2 hypersensitivity reaction.
A 35-year-old woman with myeloblastic leukemia received an allogeneic hematopoietic stem cell transplant. A month later she has now developed an extensive, scaling rash. She also has jaundice and watery diarrhea. A skin biopsy specimen shows keratinocyte apoptosis along the dermal-epidermal junction, with upper dermal lymphocytic infiltrates. Which of the following is the most likely immunologic mechanism for these complications of her stem cell transplant?
A Acute graft-versus-host disease
B Antibody-dependent cell mediated cytotoxicity
C Delayed-type hypersensitivity reaction
D Immune complex formation
E Mast cell release of cytokines
A: Her graft-versus-host disease (GVHD) is produced when the engrafted marrow is not completely matched for major histocompatibility loci and thus contains immunocompetent donor cells that can proliferate, recognize host cells as foreign, and attack host tissues. The skin, liver, and gastrointestinal epithelium are typically affected. The localized apoptosis with GVHD does not produce significant substrate proteins for amyloid formation. Delayed-type hypersensitivity is more likely seen with contact dermatitis. Immune complex formation is more typical of type III hypersensitivity with autoimmune antibody formation. Type I hypersensitivity with systemic anaphylaxis occurs with exposure to an antigen, such as penicillin, after prior exposure.
Draw a general overview of T cell activation starting from dendritic cell traveling to lymph node and ending with T cell proliferation in the lymph node. Include the terms CCR7, CXCL 19/21, MHC II, B7, CD28, CD4, and IL-2.
Got it?!
A 2-year-old boy is brought to the emergency department by his parents after they found him to be lethargic and febrile. His current symptoms started 1 week ago and initially consisted of a sore throat and a runny nose. He subsequently developed a fever and productive cough that has become worse over time. Notably, this patient has previously presented with pneumonia and gastroenteritis 8 times since he was born. On presentation, the patient's temperature is 103°F (39.4°C), blood pressure is 90/50 mmHg, pulse is 152/min, and respirations are 38/min. Based on clinical suspicion, an antibody panel is obtained and the results show low levels of IgG and IgA relative to the level of IgM. The expression of which of the following genes is most likely abnormal in this patient?
A CD40L
B STAT3
C LYST
D CD18
E NADPH oxidase
This young boy with recurrent infections and a decreased IgG to IgM ratio most likely has hyper IgM syndrome, which is caused by a defect in the gene CD40L.
An appropriate immune response to infection depends upon proper coordination of multiple signaling pathways. One important pathway is binding of CD40L on helper T-cells to CD40 on B-cells because this interaction leads to antibody class switching from IgM to IgG and IgA. Since these latter antibody types are utilized by the mature humoral immune response, patients with defective class switching (known as hyper IgM syndrome) will present with recurrent pyogenic infections, opportunistic infections, and abnormal serum antibody findings.