Session 5: Defensive Breakdown and Bone Marrow Flashcards
Be aware of the range of congenital and acquired immunodeficiency syndromes
Immunodeficiencies may be congenital or acquired and any part of the innate or adaptive immune system may be affected.
Congenital immunodeficiency is relatively rare. They may affect phagocytes, complement production/ activation, B cells, T cells or a combination.
Acquired immunodeficiency, other than AIDS, may be secondary to other diseases but it is often iatrogenic. Acquired immunodeficiency may affect phagocytes, B cell, T cells or a combination.
The most important acquired immunodeficiency syndrome is AIDS caused by human immunodeficiency virus (HIV). However, there are many other important causes of acquired immunodeficiency including leukaemia, lymphoma, multiple myeloma, splenectomy, corticosteroid therapy and chemotherapy.
How are congenital immunodeficencies managed? Give examples of B and T cell deficiency
The congenital immunodeficiencies are rare and their management is specialised. They are the province of the paediatrician and the immunologist.
B-Cell deficiency
- X-linked hypogammaglobulinaemia (Bruton syndrome): recessive, early presentation, low IgA and IgM, no tonsils
- Mature B cells are not generated => lack of antibodies
T-cell deficiency
- DiGeorge Syndrome: CATCH-22 (cardiac abnormality esp tetralogy of Fallot, abnormal facies, thymic aplasia, cleft palate, hypocalcaemia/hypoparathyroidism)
- Absent thymus (T cells unable to mature)
Describe SCID, Ataxia Telangiectasia and CGD
Severe Combined Immunodeficiency (SCID)
- Recessive, low B and T cells, treated by bone marrow transplant
- SCID involves defective antibody response due to direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells.
- Most severe form of primary immune deficiency
Ataxia telangiectasia:
- Recessive, thymic hypoplasia, low B cells (due to low T helper cells)
- Treated by bone marrow transplant
Neutrophil defect
- Chronic granulomatous disease
- X-linked recessive, persistent infections of skin, respiratory and Gi tract
- Neutrophils present but do not function properly – defective bacterial killing by neutrophils (so bacteria cannot be successfully eliminated)
- Treated by bone marrow transplant
Describe the management of acquired immunodeficiencies
The major acquired immunodeficiencies will be seen in the context of infectious disease units, haematology, oncology and transplantation
Give examples of acquired B and T cell deficiencies
Acquired B Cell Immunodeficiency
- Hypogammaglobulinaemia (low levels of all immunoglobulins) can occur in chronic lymphatic leukaemia and other lymphoproliferative disorders, myeloma (dedicated to the production of 1 immune component at the deteriment of others), nephrotic syndrome (due to loss of immunoglobulins at glomerulus)
Acquired T Cell immunodeficiency
- Can occur in HIV, chemotherapy, Hodgkin’s disease, immunosuppression e.g. transplantation
Radiotherapy, Chronic Lymphatic Leukaemia and Malnutrition can reduce both B and T cell levels.
What’s the difference between neutropenia and myelodysplasia?
Neutropenia: not enough neutrophils, risk of developing neutropenic sepsis
Myelodysplasia: present but neutrophils are not functioning
Describe HIV disease
HIV infection
Virus infects via CD4 molecule on T helper cells => decreased T helper cells (low CD4 count)
Affects T and B cell responses
Lymphopenia and alterations in T cell subsets common
Opportunistic infections
Describe the range of opportunistic pathogens in HIV
Fungal
- Pneumocystis jiroveci (Carinii) – pneumonia
- Candida albicans – GIT (thrush)
- Aspergillus fumigatus (very rarely affects healthy people, normally affects immunosuppressed hosts) – pneumonia
- Histoplasma capsulatum – disseminated
- Cryptococcus neoformans – meningo-encephalitis, pneumonia
Mycobacteria
- Tuberculosis
- Mycobacterium avium-intracellulare infection (MAI) – atypical mycobacterial infection
Parasites
- Cryptosporidia – GIT
- Isospora – colon (Cystoisospora belli)
- Toxoplasma gondii (normally completely silent in healthy people) – CNS, eyes, lymph nodes
Viral
- Cytomegalovirus (CMV) – GIT, CNS etc
- Herpes zoster – shingles
- Herpes simplex – muco-cutaneous, can affect eye
Other bacteria
- Haemophilus influenzae
- Streptococcus pneumoniae
Describe Pneumocystis Jiroveci
Atypical pneumonia in appropriate clinical setting should prompt investigation
Diagnosis by direct microscopy of broncho-alveolar lavage (inject sterile water during bronchoscopy and collect sample)
If suspicion is high, treat empirically with cotrimoxazole
Describe Candida albicans
Oral/oesophageal disease common
Occasionally systemic (usually when immune system is really low)
Diagnosed clinically – white plaques
Treatment – fluconazole or related drugs
Describe Cytomegalovirus
Usually reactivation of old infection (e.g. after low-dose steroid treatment)
Subclinical CMV common in normal people
Pneumonitis, oesophagitis, colitis, hepatitis
Treatment – acyclovir/gancyclovir
Describe Herpes Zoster and Herpes Simplex
Herpes zoster
- Shingles – reactivation
- Vesicular rash
- May be extensive and severe
- Limited by the midline, e.g. limits by the ophthalmic division of the trigeminal nerve
- May involve conjunctivae
Herpes simplex
- Skin lesions, encephalitis, systemic
- Treatment: acyclovir/gancyclovir
- Mycobacterium tuberculosis
- Common in HIV patients but all immunocompromised patients at risk
Describe MAI and EBV
Mycobacterium avium intracellulare
- May cause systemic infection, GI disturbance etc
- Large numbers of organisms usually present
Epstein Barr virus (EBV)
- Reactivation of infection common
- Post-transplant lymphoproliferative disorder
- B cell proliferation driven by EBV, due to therapeutic immunosuppression after organ transplantation
- Mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia…may progress to lymphoma
- May spontaneously regress on reduction or cessation of immunosuppressant medication, and can also be treated with addition of anti-viral therapy. In some cases it will progress to non-Hodgkin’s lymphoma and may be fatal.
Describe the JC and BK viruses
v JJC virus (John Cunningham Virus – JCV)
Human polyomavirus which is genetically similar to BK and causes progressive multifocal leukoencephalopathy (PML) and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with drugs intended to induce a state of immunosuppression (e.g. organ transplant patients).
v BK(polyoma)virus
Widespread but many people infected are symptomatic. If symptoms do appear, they tend to be mild: respiratory infection or fever. These are known as primary BK infections.
The virus then disseminates to the kidneys and urinary tract where it persists for the life of the individual. It is thought that up to 80% of the population contains a latent form of this virus, which remains latent until the body undergoes some form of immunosuppression. Typically, this is in the setting of kidney transplantation or multi-organ transplantation.
Presentation in these immunocompromised individuals is much more severe. Clinical manifestations include renal dysfunction (seen by a progressive rise in serum creatinine) and an abnormal urinalysis revealing renal tubular cells and inflammatory cells.
What are opportunistic infections and give some examples of opportunistic pathogens
Opportunistic infections are the type of infection that occurs when the immune system is compromised and is related to the defective components. Opportunistic pathogens for the types of immune dysfunction are listed below:
- Phagocyte defects: Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Candida albicans, Aspergillus fumigatus,
- Complement defects: Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Neisseria meningitidis
- Antibody deficiency: Campylobacter species, Mycoplasma species, Echovirus, Listeria, Legionella, Salmonella, Mycobacterium tuberculosis, Atypical mycobacteria, Herpes zoster, Herpes simplex, CMV, EBV, Measles, Papova viruses, Candida, Cryptococcus, Nocardia, Pneumocystis, Histoplasma
Describe the structure of bone marrow
RBC, platelets and most WBC are produced here
Soft, spongy, gelatinous tissue found in the hollow spaces in the interior of bones
Consists of stem cells supported by stroma
Red marrow (medulla ossium rubra) – mainly contains haematopoietic tissue
Yellow marrow (medulla ossium flava) – mainly fatty tissue
All marrow at birth is red
Half of marrow is red in adults, rest converted to yellow marrow (less cellular, more fat spaces)
Outline haemtopoiesis
Myeloid – white cells
- Myeloblast (high nuclear/cytoplasmic ratio) => Promyelocyte => Myelocyte => Metamyelocyte => Band cell => Neutrophil
- Similar process for eosinophils, monocytes and basophils
Myeloid – red cell
- Proerythroblasts => Early normoblast => Intermeidate normoblasts => Late normoblasts => Reticulocyte (RNA still present) => Red cell
- Haemoglobinisation of cytoplasm => nuclear maturation => finally nuclear extrusion
Describe platelet production
Megakarycotes stay in the bone marrow and produce platelets
Cells increase in size and replicates its DNA
Platelets ‘bud’ from the cytoplasm
Platelet production is controlled by thrombopoietin (TPO)
Describe the spleen including functions
Surrounded by capsule
Consists of:
- Red pulp: sinuses lined by endothelial macrophages and cords (full of reticuloendothelial cells)
- White pulp: similar structure to lymphoid follicles
Blood enters via the splenic artery
- White cells and plasma preferentially pass through the white pulp
- Red cells preferentially pass through the red pulp
Functions of the spleen (essentially a filter organ)
- Sequestration and phagocytosis – old/abnormal (damaged/defective) red cells removed by macrophages
- Blood pooling – platelets and red cells can be rapidly mobilised during bleeding (to keep circulating volume up)
- Extramedullary haemopoiesis – pluripotential stem cells proliferate during haematological stress or if marrow fails (e.g. myelofibrosis)
- Immunological function – 25% of T cells and 15% of B cells are present in the spleen
Describe hyposplenism
= Lack of functioning splenic tissue
Causes: sickle cell disease (patients are treated as if the spleen has been taken out as it becomes a withered organ), coeliac disease, splenectomy
Blood film reveals Howell Jolley bodies (DNA remnants) – cannot be removed.
Patients at risk of overwhelming sepsis, particularly from encapsulated organisms e.g. Pneumococcus, Haemophilus influenza and Meningococcus
What is Neutropenia and what are possible causes?
Neutrophil count below <1.5x10^9/L
Could be due to reduced production or increased removal. Increased removal could be due to immune destruction or splenic pooling
Reduced production
- B12/folate deficiency
- Infiltration by malignancy or fibrosis
- Aplastic anaemia
- Drugs – chemotherapy, antibiotics, anti-epileptics, psychotropic drugs, DMARDs
- Viruses
- Congenital disorders e.g. cyclic neutropenia
Describe Aplastic Anaemia
Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin (fibrosis)
Idiopathic aplastic anaemia
- Thought to be due to T-cell mediated destruction of stem cells (immune condition)
- No secondary cause found e.g. drugs, congenital disorder, viruses
