Topics A26-33 - Immunopathology: Hypersensitivity, Transplantation, Autoimmune diseases, Immune Deficiency, AIDS

Question 1

What are the alternate names for the hypersensitive reactions types I through IV?

Answer 1

Type I: Immediate

Type II: Antibody-mediated

Type III: Immune complex-mediated

Type IV: Cell-Mediated

Question 2

What are the general steps of sensitization (initial exposure) that occur the first time the body is exposed to an antigen that will later cause a type I hypersensitive reaction?
(I put it in 4 steps but that really doesn’t matter)

Answer 2

1. Antigen/allergen enters body somehow
2. Antigen taken up by APC, presents it with MHC-II to Th2 cells
3. Th2 cells activated, produce IL-4 and IL-5 to stimulate B cells (that have also detected the antigen) to undergo class switching to produce IgE that are specific to that antigen.
4. Mast cells keep IgE on their Fcε receptors

Question 3

What occurs on secondary exposure to an antigen/ allergen which has been sensitized to have a type I hypersensitive reaction? (4 things)

Answer 3

1. Within minutes, antigen binds two IgE antibodies on mast cells and causes degranulation, releasing histamine, serotonin, bradykinin, and chemotactic factors (among others)
2. Initial (“primary”) mediators cause vasodilation, increase capillary permeability, smooth muscle contraction / bronchoconstriction, and increase mucous secretion
3. Late phase reaction (2-8 hours after) - secondary mediators synthesized by mast cells and eosinophils, most importantly leukotrienes but also PDGF and TNF. Similar effects as primary mediators but last longer
4. Eosinophils also release Major Basic Protein and Eosinophilic Cationic Protein: toxic to epithelial cells, causing necrosis

Question 4

What is the most dangerous disease caused by local anaphylaxis?

What are 3 complications of it?

What condition does it lead to in the long run?

Answer 4

Asthma bronchiale: hyperreactive airways with difficult expiration. May progress to status asthmaticus (doesn’t respond to treatment)

1. Airways have vasospasm
2. Overproduce mucous (“Curshman’s spiral” mucous plug in sputum)
3. Eosinophils cause crystals to form (“Charcot-Leyden crystals”)

Long run -> emphysema

Question 5

What is the major risk to life in systemic anaphylaxis?

Answer 5

The larynx swells, causing stridor sound. The swelling can be bad enough to require a conicotomy to provide a route for air to get into the lungs.

Question 6

Besides laryngeal swelling, what is the other respiratory problem with systemic anaphylaxis?

Answer 6

Adult/Acute Respiratory Distress Syndrome (ARDS) - pulmonary edema with protein build-up

Question 7

What are three common causes of local anaphylaxis?

What are two common causes of systemic anaphylaxis?

Answer 7

Local: hay fever (pollen, cats, etc), food allergies (seafood, nuts), contact dermititis from detergents used to wash clothes

Systemic: parenteral administration of drugs, such as penicillin. Also, bee venom.

Question 8

What are two type II hypersensitive rxns associated with blood?

Answer 8

1. ABO incompatible transfusion: people have antibodies for the blood groups that they don’t have, and the infused RBCs are attacked
2. Rh- mother with Rh+ fetus: if the mother has been previously exposed and produces anti-Rh IgG antibodies, those antibodies can travel through the placenta and attack the fetal red blood cells and bone marrow, causing erythroblastalis fetalis (moderate) or hydrops fetalis (very severe)

Question 9

What are 3 mechanisms by which antibodies can cause disease? (type II hypersensitivity reaction)

Answer 9

1. Opsonization of non-harmful cells: causes complement system to attack, as well as induces phagocytosis
2. Inflammation: Complement system activated by the immune complexes also stimulates inflammation, recruiting neutrophils and monocytes
3. Cellular dysfunction: antibodies alter the function of cells in conditions like myasthenia gravis and Graves disease

Question 10

What is the problem in myasthenia gravis?

What about Graves disease?

What type of hypersensitive reactions are they?

Answer 10

Myasthenia gravis: acetylcholine receptor is targeted, preventing muscle contraction. Muscle weakness and eventual paralysis develop

Graves disease: TSH receptor is targeted, but it actually stimulates this receptor and causes hyperthyroidism (although it will eventually lead to hypothyroidism if untreated)

Type II hypersensitive reactions

Question 11

What is Goodpasture syndrome?

What type of hypersensitive reaction is it?

Answer 11

Antibodies are formed against the noncollagenous protein (NCI) of the basement membranes in the kidey glomeruli and lung alveoli. Causes bleeding from the lung and kidney failure.

Type II hypersensitive rxn

Question 12

General description of type III hypersensitivity

Answer 12

Soluble antigen-antibody (usually IgG or IgM) complex float through circulation and deposit in blood vessels, causing complement activation and acute inflammation, which lead to cell lysis, necrosis, etc. Most autoimmune diseases can cause type III hypersensitive reactions.

Can be exogenous or endogenous antigens.
Can be local or systemic deposits

Question 13

What are two important physical parameters of immune complexes that affect how they can precipitate? (May seem minor but Matolcsy really highlighted it)

Answer 13

1. Charge: if antigen-antibody complex is positively charged, it is attracted to negatively charged endothelium
2. Size: larger complex are filtered in the spleen and liver by macrophages, not causing harm. The most damaging ones are small or intermediate in size because they aren’t phagocytosed and circulate longer

Question 14

What are 3 favored sites of immune complex deposition?

What are the names of the conditions that arise from inflammation there?

Answer 14

Kidneys, joints, and small blood vessels

Causes glomerulonephritis, arthritis, and vasculitis

Question 15

What type of necrosis occurs in vasculitis caused by type III hypersensitive reaction?

What does that look like with light microscopy?

Answer 15

Fibrinoid necrosis: smudgy eosinophilic protein deposition in necrotic vessel wall

Question 16

What are the two types of Type IV hypersensitivity reactions?

Answer 16

1. Delayed hypersensitivity: Th1 memory cells mediating with cytokines inducing inflammation
2. Cytotoxic T-cell mediated: CD8+ T cells kill tissue grafts, as well as play role in type 1 diabetes killing of beta cells

Question 17

What is the most commonly-used example of delayed hypersensitivity? (from lecture and Robbins)

Answer 17

Tuberculin reaction: testing to see if a person has been sensitized to M. tuberculosis. An attenuated form of tuberculosis is injected subcutaneously, and if the person has been previously exposed, then 24-72 hours later there will be a peak in erythema and induration.

In histology, looks like “cuffing” of memory Th1 cells and macrophages secreting cytokines that create dermal edema and fibrin deposition.

Question 18

What is the result of prolonged delayed hypersensitive reactions?

Answer 18

Granulomatous inflammation.

Th1 cells secrete cytokines like IFN gamma that cause macrophages to accumulate and become epitheloid cells or giant cells. These lymphocytes form a granulomatous ring around the infection.

Older granulomas develop an enclosing ring of fibroblasts and connective tissue

Question 19

What are the three mechanisms by which the host rejects transplanted tissues?

Answer 19

1. Transplant antigens are picked up, presented, and B cells produce antibodies against them
2. Th1 cells activate macrophages against the rejection (delayed-type hypersensitive reaction)
3. CD8+ T cells recognize foreign MHC I, and so they attack the transplant with perforins, granzymes

Question 20

What are the 3 types of allograft rejection?

Answer 20

1. Hyperacute: occurs within minutes, and only occurs if patients have already been sensitized to those antigens (should not happen with proper testing)
2. Acute: takes days/week to form. Both cellular and humoral effects are possible. Renal tubulitis is the most difficult part, coordinated mostly by T cells.
3. Chronic rejection: takes years, and all transplants eventually undergo chronic rejection. Mostly the arterioles are affected: slowly start to narrow. Atrophy and fibrosis results.

Question 21

What are 2 ways we can increase survival of grafts?

Answer 21

1. Good match for HLA antigens (and to some extent ABO blood groups)
2. Immunosuppression: corticosteroids, cyclosporin. But its an infectious disease and cancer risk.
   - Specific immunosuppression: New target therapies on CD3+ cells, or blocking of costimulatory factors like the CD28-B7 connection

Question 22

What are the 3 most frequent cancer risks from specific viruses that occur with immune suppression, such as after a transplant?

Answer 22

1. Epstein Barr Virus -> lymphoma
2. Human Papilloma Virus -> cervical cancer
3. Herpes virus 8 -> Kaposi’s sarcoma

Question 23

What are the two types of bone marrow transplants?

Answer 23

1. Autologous BM transplant: patient’s own healthy bone marrow hematopoetic stem cells (HSC) are cultivated, kept and frozen. Then the patient given irradiation or chemotherapy to kill his basically all the leukocytes and HSCs in the body. Then the HSCs cells are put back in to repopulate the bone marrow
2. Allogenic BM transplant: same idea, but with foreign donor HSC

Question 24

What unique complication can occur from allogenic bone marrow transplantation?

What two forms of this can occur?

Answer 24

Graft vs Host Disease (GVHD) - the graft’s T cells begin to produce antibodies against recipient tissues

Acute GVHD: days-weeks after transplant. Epithelial cell necrosis, jaundice, mucosal ulceration, diarrhea, generalized rash

Chronic GVHD: may occur after acute or on its own later. Has skin lesions, may look like other autoimmune disorders

Question 25

What are the two forms of immunological tolerance?

Answer 25

1. Central tolerance: in the thymus, bone marrow, and lymph nodes T and B cells are killed if they bind to self antigens
2. Peripheral tolerance: outside of the central areas there is death or inactivation of self-reactive lymphocytes, such as by anergy, suppression by Treg cells, or activation-induced cell death

Question 26

What is the function of the AIRE gene?

Answer 26

AIRE = AutoImmune REgulatory gene. Mutations in this gene allow some self-reactive T cells to escape deletion

Question 27

What is anergy?

Answer 27

Functional inactivation (rather than death) of self-reactive lymphocytes when their costimulatory factors are blocked (e.g. APC lacking B7)

Question 28

What are some cytokines that regulatory T cells use to suppress the immune system?

Answer 28

Immunosuppressive cytokines: IL-10, TGF

(If Treg cells have a mutated gene for the transcription factor FoxP3, then Treg cells are deficient and an autoimmune disease develops called IPEX: immune dysregulation, polyendocrinopathy, entropathy, X-linked syndrome)

Question 29

5 mechanisms by which autoimmune diseases bypass peripheral and central tolerance

Answer 29

1. Infectious disease leads to expression of costimulatory factors, like B7
2. Molecular Mimicry: e.g. Streptococci has cross-reacting antigens with myocardium -> Rheumatic Heart Disease
3. Molecular Modification: ROS released by leukocytes destroy host tissue, creating new epitopes which are not normally tested for self-tolerance
4. Polyclonal activation: mitogens stimulate lymphocyte proliferation without being selective. May be the result of infection
5. Reduction of T cell suppression (part of aging)

Question 30

Which population are normally affected by SLE: Systemic Lupus Erythematosus? (age, gender, ethnicity…)

Answer 30

Females (9:1 prevalence over males), up to 1 in 250 females affected, and more common in black women.

Middle-aged, 30-50 years old

Question 31

What are the three mechanisms involved in development of SLE?
(that’s the way Matolcsy worded it, but more simply it’s 3 groups of things for which people with SLE may have antibodies)

Answer 31

1. Anti-nuclear antibodies (ANA): against DNA, RNA, histones etc. Leads to type III hypersensitive reaction with circulatory immune complex disease.
2. Anti-blood cell antibodies: get type II hypersensitive reation via attacking own RBCs and other components of blood (platelets, WBCs..)
3. Antiphospholipid Antibodies: phospholipids required for clotting, so more thromboses develop

Question 32

What are “lupus anticoagulants?”

Answer 32

Because people with SLE have anti-phospholipid antibodies, during in vitro clotting tests there is decreasing clotting ability.

However, in the body, these antibodies actually lead to more clotting.

Question 33

What test might someone with SLE be false-positive for? Why?

Answer 33

May be false-positive for syphilis, because some people with SLE have anti-cardiolipin antigen which is also used on syphilis tests.

Question 34

What are two genetic defects associated with SLE?

Answer 34

1. People with HLA-DR2 or HLA-DR3
2. Defect of Classical pathway of Complement (esp. C1q, C2, or C4), resulting in defective clearance of immune complexes, apoptotic cells, and defective B cell tolerance.

Question 35

What are three environmental factors associated with SLE?

Answer 35

1. UV light: causes flareups. Possibly causes some cells to undergo apoptosis and release nuclear fragments, which antibodies attack
2. Cigarette smoking
3. Certain drugs, like penicillin (from lecture), procainamide or hydralazine (book)

Question 36

What are 3 rashes that are signs of SLE?

What do you see in histology samples of these rashes?

Answer 36

1. Malar “butterfly” rash: erythema over nose/cheeks
2. Discoid rash: erythematous raised patches
3. Sunlight-induced rash (photosensitivity)

Histo: see immune deposits with necrosis at basal layer of papillary dermis.

Question 37

What happens to the vessels of people with SLE? How does this affect organs like their brain and kidneys?

Answer 37

Necrotizing Vasculitis from immune complexes invading and necrotizing cells. Can cause thrombus, ischemia.

Also vessel fibrosis with narrow lumen, causing ischemia and atrophy to kidneys, brain, etc. May get microinfarcts of brain.

Question 38

What is the specific condition seen in the heart of people with SLE?

Answer 38

Libman-Sacks Endocarditis: vegetations / deposits of fibrin in mitral valve

Question 39

How are the serosal membranes and joints affected by SLE?

Answer 39

Both have inflammation.

Joints: non-specific synovitis, capsule has inflammatory reaction

Serosal surfaces: pericardial and pleural inflammation. Serosal exudate develops.

Question 40

How is the kidney affected in people with SLE?

Answer 40

Immune complexes precipitate in the subendothelial layer of the Bowman capsule. This causes glomerulonephritis.

Leads to hematuria, proteinuria, oliguria (produce small amount of urine), and kidney failure

Question 41

What are three immunologic abnormalities of people with SLE? (from Robbins)

Answer 41

1. Cells have been exposed to unusually high levels of IFN alpha and other type 1 interferons
2. TLR’s recognize DNA and RNA, allowing for anti-nuclear antibody production
3. B cell tolerance mechanisms fail, can be both centrally and peripherally

Question 42

What are the 3 most frequent causes of death in people with SLE?

Answer 42

Kidney failure, intercurrent infections, and cardiovascular disease

(most important part of SLE is the type III hypersensitivity with deposits in small vessels)

Question 43

What type of hypersensitivity is most important in Rheumatoid Arthritis (RA)?

Answer 43

Type IV hypersensitivity: CD4+ Th cells overreact.

May occur after infection (e.g. parvovirus, EBV, mycobacterium, borrelia..) that lead to activation of Th cells that have cytokine storm that is behind the pathogenesis of RA.

Question 44

What are 4 major effects of overproduction of cytokines that occurs in Rheumatoid Arthritis?

Answer 44

1. Rheumatoid Factor: IgM auto-antibodies form against own IgG antibodies (targets IgG Fc region)
2. Macrophages activated, release different tissue-destructive enzymes; causing inflammation
3. Cytokines cause synovia to proliferate
4. Increased expression of RANK-L, initiating osteoclast activity: degrades joints and bones

Question 45

What is the difference between how joints are affected from rheumatic fever vs rheumatoid arthritis?

What are the 2 major effects on the joint via RA?

Answer 45

Rheumatoid arthritis has stronger effects in small joints like in the finger, while rheumatic fever tends to affect big joints like the shoulder

2 major effects on joint:

1. Proliferation of synovia
2. Cartilage destroyed -> ankylosis

Question 46

How does RA progress in regards to its effects on the joints?

Answer 46

In the beginning, joints are enlarged and painful. Later they are deformed and restricted.

May see things like ulnar rotation or flexion-hyperextension abnormalities of the fingers

Question 47

How might the vessels and lungs be affected in RA?

Answer 47

Vessels: vasculitis, central fibrinoid necrosis. May have Raynauld phenomenon

Lungs: may have fibrosis in perialveolar area. This may cause cor pulmonale chronicum.

Question 48

What might develop in the subcutaneous tissue of people with rheumatoid arthritis?

Answer 48

Rheumatoid Subcutaneous Nodules: usually on forearms or areas that get mechanical pressure.

Have central area of fibrinoid necrosis, surrounded by macrophages, granulation tissue, and lymphocytes. Later replaced by sclerotic tissue.

Question 49

What is meant by “pannus” formation with RA?

Answer 49

The joint space swells as it is filled with proliferating synovial lining cells, inflammatory cells, granulation tissue, and fibrous connective tissue.

Question 50

What are the two most characteristic signs of Sjögren syndrome?

Why do these two signs occur?

Answer 50

Dry mouth (xerostomia)
Dry eye (keratoconjunctivitis sicca)

Autoimmune attack of salivary and lacrimal glands. Again it’s a Type IV hypersensitivity problem, Th cells.

(Raynauld phenomena may occur too, but less important)

Question 51

What are some consequences of dry eyes and dry mouth in Sjögren syndrome?

Answer 51

Saliva and tears are protective, antimicrobial

Get fungal infections in mouth, bacterial infections and conjuncitivitis in eye.

May also affect bronchial glands, causing bronchitis

Other glands may be affected -> sinusitis, vaginal dryness.

Question 52

What are the two types of Sjögren syndrome?

Answer 52

1. Primary form: “sicca syndrome” - isolated to just the Sjögren syndrome problems with autoimmune reaction against glands
2. Secondary form: combines with other autoimmune disorders (overlap with RA or SLE)

Question 53

What are two self-reactive antibodies that develop in Sjögren syndrome that are also common in other autoimmune diseases?

Answer 53

Anti-nuclear antibodies (ANA)

Rheumatoid Factor (RF) - targets own IgG antibody Fc regions

So these antibodies are not specific for tests of these autoimmune diseases

Question 54

What is the major risk for having Sjögren syndrome, besides the normal autoimmune effects?

Answer 54

Non-Hodgkin B cell Lymphoma

May develop as unilateral enlargement of the parotid gland

Question 55

What are the general characteristics of Systemic Sclerosis (Scleroderma, SS)?

What organs are affected?

Answer 55

Autoimmunity causing excessive fibrosis in multiple tissues, mainly the skin but also GI, kidney, heart, lung, maybe even muscle. SubQ tissue has deposits of inelastic collagen fibers, causing rigidity.

CD4+ Th related hypersensitivity (type IV)

10 year survival rate about 70%

Question 56

There’s a common acronym for the 5 main signs of Scleroderma, what is it?

Answer 56

CREST
1. Calcinosis: deposit of calcium nodules -> thickening and tightening of skin

2. Raynauld phenomenon: cold temperatures -> exaggerated vasoconstriction in fingers
3. Esophageal dysmotility: feels like food is stuck in the esophagus. May have Barrett metaplasia.
4. Sclerodactyly: thickening of skin around fingers/toes
5. Telangiectasis: dilated capillaries, “spider veins” - mostly on face, palms, mucous membranes

Question 57

What are the two types of Scleroderma?

Answer 57

1. Diffuse Scleroderma: sclerosis everywhere, rapid progression, internal organs heavily involved, bad outcome. Have antinuclear antibodies (ANA): usually anti-DNA topoisomerase I
2. Limited Scleroderma: less severe, slow progression. Have ANA: anticentromere antibodies.

Question 58

What is polyarteritis nodosa (PAN)?

Answer 58

A group of non-infectious diseases characterized by necrotizing vasculitis, usually due to immune complex deposition. Similar condition as found in SLE. Usually in small-medium size vessels. May be due to previous infectious (Hep B is common)

Strongest effects are in renal and visceral vessels.

Question 59

What is different in acute vs chronic stages of polyarteritis nodosa (PAN)?

Answer 59

Acute: transmural mixed inflammatory infiltrate, with fibrinoid necrosis + neutrophils, monocytes, luminal thrombosis

Chronic: fibrous thickening of the vessel wall

(Both can coexist at the same time though)

Question 60

What is the target of antibodies in Hashimoto thyroiditis? What is the effect, and how does it progress?

What cancer risk does it have?

Answer 60

Anti-TSH receptor, thyroglobulin, or thyroid peroxidase

At beginning of disease, tissue is destroyed and everything is released -> hyperthyroid symptoms

Afterwards the thyroid function is inadequate and replaced with fibrotic tissue, so hypothyroidism results.

Also has risk for B cell lymphoma

Question 61

What are the four primary (hereditary) immune deficiency diseases that Matolcsy mentioned in lecture?
[note there are many others in Robbins!]

Answer 61

1. Bruton disease / X-linked agammaglobulinemia (XLA). No mature B cells produced.
2. DiGeorge Syndrome: thymus underdevelopment, no T cell development. Especially prone to viral infection.
3. Swiss-type Agammaglobulinemia: Cytokine receptor mutation, no T and B cell function. Need bone marrow transplant.
4. Isolated IgA deficiency: problem with isotype switching to IgA. GI, respiratory problems.

Question 62

Bruton Disease:

• What population is more affected?
• What is a characteristic change in the lymph nodes?
• What is the main risk, besides infection?

Answer 62

Males affected (because it’s X-linked)

Lymph node follicles lack germinal centers because there are no B cells

May develop rheumatoid arthritis because T cells try to compensate for lack of B cells, and may overreact -> autoimmunity

Question 63

Which enzyme is nonfunctional in Bruton disease? How does that work?

Why don’t babies born with Bruton disease show symptoms immediately when born?

Answer 63

Bruton Tyrosine Kinase (BTK) is nonfunctional.

The tyrosine kinase is associated with the pre-B cell receptor and it’s signal transduction. Without that enzyme, the pre-B cell receptor cannot signal the cells to proceed along with maturation.

Don’t show symptoms when born because maternal immunity protects them until they are ~6 months old.

Question 64

Which type of HIV is endemic to North America and Europe? Which type is more in Africa?

Answer 64

HIV1 is more pathogenic and widespread: seen in North America, Europe, etc. HIV2 is mainly seen in West Africa.

Question 65

Populations prone to HIV: which one is most at risk, and what about 4 other populations?

Answer 65

1. Most at risk: men who have sex with other men. HIV is concentrated in sperm, and the rectum is fragile / prone to bleeding
2. Females, especially sex workers, can contract it for the same reasons as homosexual sex. The poorest places in the world have the highest HIV rates, mostly from heterosexual sex. (Extreme poverty should be listed, but it’s not)
3. IV drug users sharing needles. But HIV dies quickly when exposed to air (HepC is other major risk)
4. People who need blood transfusions or drugs made from blood. Less of a problem now with good testing.
5. Children getting transplacental infection from mother. Some drugs can prevent this.

Question 66

What type of virus is HIV?
What are 3 viral enzymes it has?
What are the important protein and 2 important glycoproteins to know?

Answer 66

Retrovirus. Reverse transciptase with glycoprotein cover.

Enzymes: Reverse transciptase, protease, integrase.

Protein: p24 is viral antigen, used for diagnosis

Glycoproteins: GP-120 and GP-41 used to infect cells

Question 67

What are the 3 phases of HIV infection?

Answer 67

1. Infective Stage: acute, initially have flu-like symptoms for a few days, then symptoms disappear. CD4+ memory Th cells of the mucosa are infected, then this spreads to lymph nodes
2. Latency phase (chronic). Patient has no symptoms, but the virus has been produced and the person can infect others via sexual or blood-to-blood contact
3. AIDS stage: Th cells and macrophages produce large amount of virus, and they are dying. Get opportunistic infections, sepsis, certain cancers, encephalitis

Question 68

How does the HIV virus infect cells? Why do cells die from HIV infection?
[The explanation is more than Matolcsy gave, but a lot less than the book.. just some general things]

Answer 68

CD4 is a high-affinity receptor for the virus, and GP-120 binds the Th cell coreceptors to facilitate entry. GP-41 also helps the virus insert into the host cell, becoming a part of the host genome of proliferating T cells. Activated T cells end up producing a lot of viral DNA that buds off, taking some membrane with it and killing the cell. So, when T cells are needed to help protect against infection, stimuli from infections end up actually causing the HIV-infected T cells to die.

CD4+ Th cells then infect other CD4+ cells, like macrophages and DCs. Antibodies are produced against the virus, which makes macrophages internalize the virus and produce them as well.

Question 69

What two cancers are typical of HIV / AIDS patients?

Answer 69

1. Kaposi’s Sarcoma: angiosarcoma of the skin related to human herpes virus 8 (HHV8)
2. Non-Hodgkin Lymphoma: Burkitt lymphoma, diffuse large B cell lymphoma

(cervical carcinoma may be worth mentioning too, from HPV)

Question 70

Opportunistic infections from HIV:
-What is a major protozoal infection risk?
-What are 3 fungal risks?
-What are 5 bacteria and 3 viruses?
(I know this type of questioning sucks, prob don’t have to know all of them but just try to be familiar)

Answer 70

Protozoa: Toxoplasmosis

Fungal infections: pneumonia from P. jiroveci, candidiasis, histoplasmosis

Bacteria: atypical mycobacteria (M. avium), Nocardiosis, Salmonella, S. pneumoniae, H. influenzae

Viruses: Cytomegalovirus, Herpes simplex, Varicella-zoster