Tbl Flashcards
dyspnea
Difficult breathing
hemoptysis
Coughing blood
pruritis
Itching
purpuric maculopapular
Purple rash
Disseminated varicella infection is a rare disease seen in
immunocompromised
patients
Disseminated infection with varicella presents as
pneumonia, hepatitis, intravascular coagulopathy, encephalitis
Themortalityrateofdisseminatedvaricellainfectionis
55%
A depletion in the body’s natural immune system, or in some component of it.
Immunodeficiency
Having an immune system that has been impaired by disease or treatment
Immunocompromised
Having the capability to suppress the immune system, capable of immunosuppression.
Immunosuppressive
Any infection that arises subsequent to a pre- existing infection; but especially a nosocomial infection
Secondary infection
Nosocomial
A disease originated in a hospital
is a state in which the immune system’s ability to fight infectious disease is compromised or entirely absent
Immunodeficiency (or immune deficiency)
…………..Deficiencies more frequent than……………
Acquired deficiencies
primary immune deficiencies
problems of the immune system that are not genetic and which are caused by external factors.
Secondary immune deficiencies or acquired deficiencies
A person who is undergoing immunosuppression or whose immune system is weak for other reasons is said to be
immunocompromised
Reasons for weak immune system
chemotherapy, HIV, and Lupus
Distinction between primary versus secondary immunodeficiencies are based on
whether the cause originates in the immune system itself or is it due to insufficiency of a supporting component of it or an external decreasing factor of it
In most acquired cases, withdrawal of the external condition causing the deficiency can result in
restoration of immune function
most serious Acquired immunodeficiency is
HIV
most frequent causes of secondary immunodeficiencies in developed countries are
cancers involving the bone marrow and various therapies
……. results in deficiencies of virtually all components of the immune system and is a common cause of immunodeficiency in developing countries.
Protein-calorie malnutrition
Immunosuppressive drugs used to prevent ……and drugs for……, including some of the newer therapies (e.g……..&……) are causes of acquired immunodeficiencies
graft rejection
inflammatory diseases
TNF antagonists, costimulation blockade
How does human immunodeficiency virus infection (HIV) cause acquired immunodeficiency
Depletion of CD4+ helper T cells
How do irradiation and chemotherapy cause acquired immunodeficiencies
Decreased bone marrow precursors for all leukocytes
How dos immunosuppressives for graft rejection and inflammatory diseases cause acquired immunodeficiency
Depletion or functional impairment of lymphocytes
How does involvement of bone marrow by cancers cause acquired immunodeficiency
Reduced site of leukocyte development
How does proteins calories malnutrition causes acquired immunodeficiency
Metabolic derangements inhibit lymphocyte malnutrition and function
How does removal of spleen cause acquired immunodeficiency
Decreased phagocytosis of microbes
Bone marrow affecting cancer
Metastases, leukemia
Iatrogenic
Illness caused by medical examination or treatment
Iatrogenic immunosuppression is most often due to
drug therapies that kill or functionally inactivate lymphocytes or block the function of cytokines made by innate immune cells and lymphocytes.
The most commonly uses anti inflammatory and immunosuppressive drugs are
corticosteroids and cyclosporine, respectively
Widely used immunosuppressive
Anti cytokines antibodies
Various chemotherapeutic drugs are administered to patients with cancer, and these drugs are usually……. to proliferating cells, including…….
Cytotoxic
mature and developing lymphocytes as well as other leukocyte precursors.
Cancer chemotherapy is almost always accompanied by
y a period of immunosuppression and risk for infection.
Many specific diseases directly or indirectly cause immunosuppression, like :
• Many types of cancer, particularly those of the bone marrow and blood cells
(leukemia, lymphoma, multiple myeloma),
• Certain chronic infections.
Bone marrow tumors, including cancers metastatic to marrow and leukemias that arise in the marrow, may interfere with……. In addition, tumors may produce substances that interfere with…….
the growth and development of normal lymphocytes and other leukocytes
lymphocyte development or function.
Viruses that impair immune responses
Measles, human T cell lymphotropic virus 1 (HTLV-1)
They both do so by infecting lymphocytes
cancer treatment that can temporarily affect bone marrow.
Radiotherapy
Chronic infections with Mycobacterium tuberculosis and various fungi frequently result in
anergy to many antigens
Chronic parasitic infections may also lead to …… for example……
immunosuppression
depressed T cell function, in chronic malarial infections
Reasons for spleenectomy
treatment of certain hematologic diseases such as autoimmune hemolytic anemia and thrombocytopenia, in which red cells and platelets, respectively, are destroyed by phagocytes in the spleen, or infarction in sickle cell disease.
Patients without spleens are more susceptible to infection by some organisms, particularly bacteria such as…..&……. which have …………..rich capsules and are normally cleared by…….
pneumococci and meningococci,
polysaccharide-rich capsules
opsonization and phagocytosis.
One secondary immunodeficiency that has been recognized for some time but has an unknown cause is
hypogammaglobulinemia
hypogammaglobulinemia is confused with
CVID, a condition that shows genetic predisposition
Common variable immunodeficiency
Symptoms of hypogammaglobulinemaia
recurrent infection
hypogammaglobulinemaia typically manifests in
young adults who have very low but detectable levels of total immunoglobulin with normal T-cell numbers and function (some cases do involve T cells defects which grow more severe)
natural factors in immune function
Extremes of age
The very young and elderly suffer from impairments to immune function not typically seen during the remainder of the life span
How can diabetes result in an immunodeficiency disorder
because white blood cells do not function well when the blood sugar level is high
Other Causes of immunodeficiency
• Trauma • Injections • Operative and other incisions • Internal foreign bodies • Major surgery • Monoclonal antibodies and related small molecules • Transfusion (which may lead to iron overload) • Environmental toxins • Excess weight . Chronic disease . Chronic mental stress . Lack of sleep
How does Chronic mental stress cause immunodeficiencies
Stress releases hormones like cortisol that suppresses inflammation (inflammation is initially needed to activate immune cells) and the action of white blood cells.
How does lack of sleep cause immunodeficiencies
Sleep is a time of restoration for the body, during which a type of cytokine is released that fights infection; too little sleep lowers the amount of these cytokines and other immune cells.
Protein-calorie malnutrition is associated with
impaired both innate and adaptive immunity
Much of the morbidity and mortality in malnourished people is due to
infections
hypoproteinemia is associated with depression in
T-cell numbers and function
Primary malnutrition leads to
atrophy of the lymphoid organs, profound T-lymphocyte deficiency, and increased susceptibility to pathogens, reactivation of viral infections, and development of opportunistic infections.
imbalance between the nutrients the body needs and the nutrients it gets.
Malnutrition
types of malnutrition
overnutrition
Under nutrition
Animal studies have found that deficiencies in …….can alter immune responses
zinc, selenium, iron, copper, folic acid, and vitamins A, B6, C, D, and E
Examples of Secondary Immunodeficiencies
Endocrine
Gastrointestinal
Hematologic
Diabetes millitus
Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy
Aplastic anemia, cancers (eg, chronic lymphocytic leukemia, multiple myeloma, Hodgkin lymphoma), graft-vs-host disease, sickle cell disease, splenectomy
Examples of Iatrogenic immunodeficiencies
Certain drugs, such as chemotherapeutic drugs, immunosuppressant’s, corticosteroids; radiation therapy; splenectomy
Examples of nutritional immunodeficiencies
Alcohol use disorder, undernutrition
Physiologic reasons of immune deficiency
Physiologic immunodeficiency in infants due to immaturity of the immune system, pregnancy
Renal examples of immunodeficiencies
Nephrotic syndrome, renal insufficiency, uremia
Rheumatologic examples of immunodeficiency
Systemic lupus erythematosus
Infectious reasons of immunodeficiency
Viral infections (eg, cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella- zoster virus), bacterial infections, rare bacterial infections with superantigens (antigens that can activate large numbers of T cells, resulting in massive cytokine production, most notably from Staphylococcus aureus), mycobacterial infections
Barrier defects of the mucous membranes are critical for the pathogenesis of respiratory, gastrointestinal, and urinary tract infection. This is associated with changes in
microbial flora.
T-cell defects and thymic function in malnutrition are similar to that seen in
congenital thymic aplasia
Primary immunodeficiencies (PIDs) are now included under the term
inborn errors of immunity
IEI
How many defined IEI
450 genetically defined diseases.
transient or persistent impairment of the function of cells or tissues of the immune system, caused by factors that are not intrinsic to the immune syste
Secondary immunodeficiency
In the last five decades, the most studied secondary immunodeficiency has been…. that’s caused by …..
acquired immunodeficiency syndrome (AIDS)
HIV
HIV infected individuals who receive….. retain their immune function and do not develop AIDS
antiretroviral therapy
individuals who receive antiretroviral therapy can still get
chronic inflammation that contributes to
the development of comorbidities: non-AIDS malignancies, cardiovascular events, renal
and hepatic diseases, bone disorders and neurocognitive impairment.
is the most prevalent cause of immunodeficiency worldwide
Malnutrition
Laboratory testing indicated in the assessment of immunodeficiency includes
blood cell counts and lymphocyte phenotyping to measure neutrophils, monocytes, T cells, B cells and NK cells. Measurement of serum immunoglobulins G, A, M and E levels and antibody responses to prior immunizations for humoral immunity and Serum albumin and total protein level.
Serum albumin and total protein levels tests are useful to identify……, which raises the suspicion of either……
malnutrition or hypoproteinemia
protein-losing diseases.
The management of a patient with secondary immunodeficiency should be focused on
improvement of the primary condition, and when possible, the removal of the offending environmental factor
when protein-losing enteropathy leads to hypogammaglobulinemia, what should be treated
treatment of the enteropathy restores normal serum immunoglobulin levels.
General measures to consider for the patient with a secondary immunodeficiency include measures to
reduce exposure to infections, antibiotic prophylaxis, and immunoglobulin replacement and immunizations.
Examples of antiinflammatory and immunosuppressive small molecule agents
corticosteroids, methotrexate, cyclosporin
Groups of immunosuppressive medications
- antiinflammatory and immunosuppressive small molecule agents
- protein kinase inhibitors and biological agents
Examples of protein kinase inhibitors and biological agents
anti- CD20 antibodies
Glucocorticoids is a type of
corticosteroids
representatives of immunosuppressive anti inflammatory medications and kinase inhibitors/biological agents respectfully
glucocorticoids and rituximab
Glucocorticoids are widely used because of their
potent anti-inflammatory action that results in reduction of symptoms in autoimmune and allergic disease
……..&……….are two of the most used medications of antiinflammatory and immunosuppressive small molecule agents
Prednisone and dexamethasone
Prednisone and dexamethasone immunosuppressive action is mediated by multiple molecular mechanisms, such as
inhibition of NFK beta pathways, followed by the suppression of the proinflammatory cytokines IL-1, IL-2, IL-6, TNF-α and IFNγ, and prostaglandins.
glucocorticoids induce……, increased …..and release of ….from the bone marrow, which is translated into lymphopenia and neutrophilia. Glucocorticoids reduce ……and other mediators of allergic disease.
anergy and apoptosis of lymphocytes
neutrophil detachment from the endothelium into the peripheral blood
immature neutrophils
histamine secretion, IgE, IL-4, IL-5
Immunosuppression is proportional to…
the duration of treatment and to the dose.
Side effects of glucocorticoids
cataracts, osteoporosis, adrenal axis suppression, hypertension, Cushing syndrome and diabetes mellitus.
The use of topical forms of glucocorticoids, such as…… significantly reduce the risk of these adverse effects because of
ointments and nasal sprays
their minimal systemic bioavailability
biological agents might be classified in
monoclonal antibodies and competitive inhibitors of receptor binding.
most prescribed biological agents.
Anti-CD20 antibodies and tumor necrosis factor (TNF)-alpha inhibitors
Six anti-CD20 monoclonal antibodies have been developed:
rituximab, veltuzumab, ocrelizumab, ofatumumab, binutuzumab and ublituximab.
first agent of this group to be developed for clinical use.
Rituximab
Side effects of Rituximab
hypogammaglobulinemia and increased risk of infections
….% patients in a tertiary care center receiving at least one dose of rituximab developed infections.
….% had low serum IgG level and….% had persistently low B cell counts one year after stopping rituximab.
47.9%
13.7%
51%
clinical indication for the use of rituximab, such as refractory autoimmune cytopenia might represent
manifestation of an IEI.
the assessment of humoral immunity before rituximab treatment has been suggested to rule-out a….
preexisting antibody deficiency.
Before taking rituximab……… should be considered in patients with recurrent infections or a severe depression of the humoral immune function.
antibiotic prophylaxis and immunoglobulin supplementation
…..monoclonal antibodies binding TNF-alpha and….. fusion protein TNF- alpha receptor antagonist have been approved for the treatment of…
4, 1
inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis and psoriasis.
major concern with the use of these biological agents is
the central role of TNF-alpha in anti-mycobacterial immunity.
To reduce their risk of tuberculosis reactivation and severe disease, patients receiving TNF-alpha inhibitors are recommended to undergo
tuberculosis screening before treatment and receive antibiotic prophylaxis if the screening is positive.
Other drugs are associated with harmful effects in the immune system that are not clearly related to the pharmacologic activity of the molecule
antiepileptic medications -phenytoin, carbamazepine, levetiracetam- may cause antibody deficiency
persistent antigen stimulation induces decreased T cell effector functions, a condition known as
T cell exhaustion.
HIV Targets ….. and induces….
CD4 T cells
T cell lymphopenia
HIV infection targets CD4 T cells and induces T cell lymphopenia through several mechanisms:
HIV-induced apoptosis, apoptosis caused by nonspecific immune activation, viral cytopathic effect, T cell cytotoxicity to HIV-infected cells and autophagy
Because of advances in……, HIV infection can now be controlled but not eradicated
anti-retroviral therapy
HIV infects other cells expressing CD4, such as……. which become………
microglial cells, liver Kupffer cells and renal tubular epithelial cells
viral reservoirs(pools)
HIV patients receiving anti-retroviral therapy often have
Incomplete immune-reconstitution of CD4 T cells with a predominant proportion of activated cells
In most treated HIV patients chronic inflammation is common, leading to
development of malignancies, metabolic syndrome and cardiovascular disease
Measles virus
Measles is a highly infectious virus shown to result in immunosuppression that can persist for
months to years after initial infection in immunocompetent hosts
Proposed mechanisms of measles immunosuppression include
T and B cell lymphopenia, inhibition of lymphocyte proliferation, skewing towards T helper 2 cytokine responses and decreased B cell and T cell memory cells
immunosuppressive effect of measles was initially demonstrated over a hundred years ago, when
it was noted a loss of the tuberculin skin test positive response during the acute phase of measles infection
Mycobacterium tuberculosis infection affects …..%
one third of world’s population
….. leading cause of mortality by an infectious disease.
Mycobacteria
In Mycobacterium tuberculosis Apoptosis and necrosis of antigen presenting cells are accelerated due to
mycobacteria replication
Patients with mycobacterial infection demonstrate decreased…….., increased production of …..and suppression of…….
lymphoproliferative responses
IFN-γ
IL-17+ CD4 T cells
Furthermore, damaging inflammatory reactions induces significant regulatory T cell activity, which attenuates the ability of
monocyte-derived and alveolar macrophages to restrict mycobacterial growth
The COVID-19 pandemic, caused by
severe acute respiratory syndrome coronavirus 2
Several changes in the immune system have been reported in patients with severe SARS Cov-2 infection like
impaired IFN-alpha signaling, reduced number and function of NK cells, and peripheral CD4 and CD8 T cell lymphopenia.
In severe COVID19 cases, a massive inflammatory response develops in …. with …. cytokines increase which causes…
The lungs
Serum
T cell exhaustion, lung tissue destruction and hypoxia,
The infant mortality due to sepsis is….. per 100,000 live births in the United States
16.1
all immune parameters are lower at birth than in adulthood except for
lymphocyte and neutrophil cell count
Neonatal adaptive immunity is biased towards the…… immune phenotype rather than ….phenotype.
T helper 2 (TH2)
TH1
Peripheral blood mononuclear cells from newborns demonstrate reduced ……..responses with decreased production of……
Tolllike receptor (TLR)
pro-inflammatory cytokines.
Neutrophils from neonates have decreased expression of surface adhesion molecules leading to……
impaired tissue migration,
Impaired production of IL-12p70 in neonates results in
non-productive activation and failure to differentiate into effector cytotoxic T cells
The protective maternal IgG that is mostly transferred during the
third trimester is limited in the premature
responses to scheduled immunizations for pre term neonates are adequate, with exception of the
hepatitis B vaccine for newborns under 2000g
Immune system changes due to aging, or immunosenescence, include
decreases in the TLR function, chemotaxis, phagocytosis and cytokine production
NK cells from elderly population are predominantly the mature CD14+CD56+bright subset with reduced
cytotoxicity function, cytokine function and migration capacity.
Aging of the adaptive immune system is often described as a shift from
naïve to memory T and B cells
infections lead to malnutrition as result of
limited food intake and absorption
Direct effects of malnutrition in lymphoid organs include
thymic atrophy, thymocyte apoptosis, decreased levels of secretory IgA and reduced cellularity in the spleen and lymph nodes.
Children with protein energy malnutrition (PEM) have shown reduced serum levels of
IL-1, IL-6, TNF-and complement system components and impaired neutrophil chemotaxis and function, NK cell cytotoxicity and dendritic cell maturation.
malnourished individuals show reduced numbers of
memory and effector T cells, reduced delayed type hypersensitivity, impaired T cell responses and fewer circulating B cells.
Protein-losing enteropathy (PLE) occurs secondary to
gastrointestinal (GI) loss of protein
We consider IgG replacement for patients with low
Less than 2 standard deviations below the mean
IgG level or absent responses to pneumococcal immunization
Uremia causes dysfunction in dendritic cells which causes
Decreased antigen presentation and co stimulaton
Uremia causes dysfunction in monocytes which causes
Decreased phagocytosis
Uremia causes dysfunction in nk which causes
Decreased Activation
Uremia causes dysfunction in neutrophils which causes
Increased apoptosis, TLR2, TLR4 expression
Uremia causes dysfunction in B cells which causes
Decreased naive B cells population, B cells activation, increased apoptosis
Uremia causes dysfunction in T cells which causes
Decreased function of effector T cells, decreased naïve t cell population, decreased IL2 Production, increased CD4+ CD28 T cell population
Vitamin D deficiency causes
Increased risk of respiratory infections in children
Vitamin E deficiency causes
Reduced infections of the elderly
Vitamin c deficiency causes
Exaggerated inflammation in murine models
Vitamin a deficiency causes
Impaired epithelial barrier function
Reduced CD4 & CD8 T cells
Zinc deficiency leads to
Thymus apoptosis Lymphopenia Reduced Th1 cytokines Impaired phagocytosis Impaired mucousal immunity
hypogammaglobulinemia is treated by
immunoglobulin therapy
hypoproteinemia is associated with
depression in T-cell numbers and function
the profound fall in cell - mediated immunity that accompanies measles infection has been attributed to specifi c suppression
of
IL - 12 production by viral cross - linking of monocyte surface CD46
Spleen function
antibody production
Acts as a filter to remove pathogens through phagocytic cells
Infections associated with asplenia include
sepsis with encapsulated bacteria, namely, S. pneumoniae and H. influenzae, and with Babesia, a protozoan that infects erythrocytes and causes fever and hemolysis with asplenia, malaria infection can be more severe
Diabetes Mellitus usually affects…. system and it causes
Innate
Effects in neutrophil functions and NET formation
Low cytokines production
Space travel causes
CD4 and CD8 T cell lymphopenia and impaired CD4 T cell function
Thymectomy in infants results in
T cell lymphopenia, with CD4 T cells typically affected more than CD8 T cells
